COVID-19 (Coronavirus Disease 2019) is the acute infectious respiratory disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Cell entry depends on viral spike protein binding to ACE2 and TMPRSS2-mediated spike priming on airway and alveolar epithelium. Clinical presentation ranges from asymptomatic infection through self-limited upper-respiratory illness to bilateral viral pneumonia, hypoxemic respiratory failure with acute respiratory distress syndrome, and multisystem involvement. A defining molecular feature of SARS-CoV-2 pathogenesis is the Nsp3 macrodomain (Mac1), a conserved viral mono-ADP-ribosylhydrolase that reverses host PARP-mediated antiviral ADP-ribosylation downstream of the interferon response. This entry models the acute infection only; post-acute sequelae are curated under the separate Long COVID entry.
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name: COVID-19
creation_date: "2026-05-26T18:00:00Z"
synonyms:
- Coronavirus Disease 2019
- SARS-CoV-2 Infection
- Acute SARS-CoV-2 Infection
description: >-
COVID-19 (Coronavirus Disease 2019) is the acute infectious respiratory disease
caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Cell
entry depends on viral spike protein binding to ACE2 and TMPRSS2-mediated
spike priming on airway and alveolar epithelium. Clinical presentation ranges
from asymptomatic infection through self-limited upper-respiratory illness to
bilateral viral pneumonia, hypoxemic respiratory failure with acute
respiratory distress syndrome, and multisystem involvement. A defining
molecular feature of SARS-CoV-2 pathogenesis is the Nsp3 macrodomain (Mac1),
a conserved viral mono-ADP-ribosylhydrolase that reverses host PARP-mediated
antiviral ADP-ribosylation downstream of the interferon response. This entry
models the acute infection only; post-acute sequelae are curated under the
separate Long COVID entry.
categories:
- Infectious Disease
- Viral Disease
- Respiratory Disease
parents:
- coronavirus infectious disease
disease_term:
preferred_term: COVID-19
term:
id: MONDO:0100096
label: COVID-19
infectious_agent:
- name: Severe acute respiratory syndrome coronavirus 2
infectious_agent_term:
preferred_term: SARS-CoV-2
term:
id: NCBITaxon:2697049
label: Severe acute respiratory syndrome coronavirus 2
description: >-
SARS-CoV-2, the betacoronavirus identified in Wuhan in December 2019 and the
sole agent of COVID-19. Cell entry depends on spike binding to ACE2 with
TMPRSS2-mediated priming on airway and alveolar epithelium.
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel
betacoronavirus, the 2019 novel coronavirus (2019-nCoV).
explanation: >-
The first clinical case series attributes the Wuhan pneumonia cluster to the
novel betacoronavirus subsequently named SARS-CoV-2.
- reference: PMID:32393804
reference_title: Real-time tracking of self-reported symptoms to predict potential COVID-19.
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: >-
COVID-19 is an acute respiratory illness caused by the novel coronavirus
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
explanation: >-
States the established aetiology of COVID-19 by its current virus name. The
sentence frames the study rather than reporting its result, so it is graded
as background.
transmission:
- name: Person-to-person transmission among close contacts
description: >-
SARS-CoV-2 spreads from person to person by the respiratory route during close
contact, which was established from the earliest Wuhan case clusters and drove
the pandemic.
evidence:
- reference: PMID:31995857
reference_title: "Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
On the basis of this information, there is evidence that human-to-human
transmission has occurred among close contacts since the middle of December
2019.
explanation: >-
Analysis of the first 425 confirmed cases establishes human-to-human
transmission among close contacts as the mode of spread.
- name: Household transmission
description: >-
Sustained close contact within a household is a high-risk exposure, with
roughly a third of household contacts of a confirmed case becoming infected in
early studies.
evidence:
- reference: PMID:32283139
reference_title: Household transmission of SARS-CoV-2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The rate of secondary transmission among household contacts of patients with
SARS-CoV-2 infection was 30%.
explanation: >-
Quantifies secondary attack among household contacts of 85 confirmed cases,
evidence of efficient transmission during prolonged close contact.
mechanistic_hypotheses:
- hypothesis_group_id: nsp3_mac1_essentiality_model
hypothesis_label: Nsp3 Mac1 Macrodomain Essentiality Model
status: CANONICAL
description: >-
The SARS-CoV-2 Nsp3 macrodomain (Mac1) is a conserved coronavirus
mono-ADP-ribosylhydrolase that is essential for pathogenesis. By
hydrolyzing PARP9/DTX3L-deposited mono-ADP-ribose marks on host proteins,
Mac1 neutralizes the effector branch of the host interferon antiviral
program and is required for productive replication in vivo. This is the
disease-level instantiation of the
parp_parg_macrodomain_viral_evasion module's canonical countermeasure
hypothesis.
evidence:
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mac1 is essential for pathogenesis in multiple animal models of CoV
infection
explanation: >-
In vivo essentiality across multiple coronavirus models directly supports
the canonical Mac1 essentiality hypothesis.
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the cellular function of the SARS-CoV-2 Nsp3 macrodomain is to hydrolyze
this end product of IFN signaling, rather than to suppress the IFN
response itself
explanation: >-
Russo et al. position Mac1 at the effector end of the IFN antiviral
cascade, consistent with the canonical countermeasure model.
- hypothesis_group_id: endotheliopathy_centred_pathophysiology_model
hypothesis_label: Endotheliopathy-Centred Pathophysiology Model
status: EMERGING
description: >-
Severe COVID-19 is increasingly framed as an endotheliopathy in which
SARS-CoV-2-driven endothelial activation, thrombo-inflammation, and
parenchymal injury — rather than direct cytopathic respiratory infection
alone — define the lethal disease phenotype. Under the interactome-rebalancing
framing, the lung endothelial interactome shifts toward a
pro-thrombotic, hyper-inflammatory state that sits downstream of viral
entry but upstream of multi-organ dysfunction. This hypothesis is parallel
to (not subsumed by) the macrodomain countermeasure model: Mac1 explains
immune evasion at the cellular level, while endotheliopathy explains
organ-scale pathology and many of the distinctive thrombotic complications.
evidence:
- reference: PMID:33965003
reference_title: "The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
evidence for many distinctive mechanistic features indicates that
COVID-19 constitutes a new disease entity, with emerging data
suggesting involvement of an endotheliopathy-centred pathophysiology
explanation: >-
Osuchowski et al. Lancet Respir Med review positions endotheliopathy
as the unifying pathophysiological framework for severe COVID-19,
distinct from purely respiratory cytopathic injury.
- reference: PMID:33965003
reference_title: "The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Such complex manifestations suggest that SARS-CoV-2 dysregulates the
host response, triggering wide-ranging immuno-inflammatory, thrombotic,
and parenchymal derangements.
explanation: >-
Directly supports the multi-system, interactome-rebalancing framing of
severe COVID-19 as a host-response dysregulation rather than direct
viral cytopathology alone.
- hypothesis_group_id: mac1_allosteric_pivot_model
hypothesis_label: Mac1 Allosteric Conformational Pivot Model
status: EMERGING
description: >-
The conserved Mac1 fold across coronaviruses (SARS-CoV-2, SARS-CoV,
MERS-CoV) supports treating Mac1 as a thermodynamic pivot point rather
than only an active-site target. Allosteric stabilization of distinct
Mac1 conformational states or PROTAC-based physical degradation would
rebalance the host interactome toward antiviral ADP-ribosylation, with
potential broad anti-coronavirus activity that active-site inhibition
alone may not achieve. Active drug-discovery programs (including the
third CACHE community challenge) have established Mac1 as a tractable
structural target with hundreds of crystallographically characterized
ligands, providing a strong starting point for conformational-pivot
chemistry.
evidence:
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus
(MERS-CoV) Mac1 domains exhibit similar structural folds, and all 3
proteins bound to ADP-ribose with affinities in the low micromolar
range
explanation: >-
Structural conservation of Mac1 across coronaviruses supports the
feasibility of a pan-CoV pivot-control strategy beyond active-site
inhibition.
- reference: PMID:40964377
reference_title: "Structure-based discovery of inhibitors of Mac1 domain of nonstructural protein-3 of SARS-CoV-2 by machine learning-augmented screening of chemical space."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Significant efforts have been recently dedicated to the discovery of
small molecule inhibitors against the Macrodomain 1 (Mac1) of
nonstructural protein 3 (NSP3) as potential antivirals for SARS-CoV-2.
explanation: >-
Ban et al. and the CACHE3 challenge directly demonstrate that Mac1 is
an active drug-discovery target with community-wide investment,
supporting the feasibility of allosteric and PROTAC-warhead programs.
- reference: PMID:40964377
reference_title: "Structure-based discovery of inhibitors of Mac1 domain of nonstructural protein-3 of SARS-CoV-2 by machine learning-augmented screening of chemical space."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Our results illustrate the effectiveness of ML-accelerated docking to
rapidly identify novel chemical series and provide a strong foundation
for the development of SARS-CoV-2 NSP3 Mac1 inhibitors.
explanation: >-
The community-level chemistry infrastructure for Mac1 hit-finding
lowers the experimental barrier for the proposed Mac1 conformational
pivot experiment.
- reference: PMID:38260573
reference_title: "Mutation of a highly conserved isoleucine residue in loop 2 of several β-coronavirus macrodomains indicates that enhanced ADP-ribose binding is detrimental to infection."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2
were highly attenuated in both cell culture and mice, indicating that
this isoleucine residue acts as a gate that controls ADP-ribose binding
for efficient virus replication.
explanation: >-
Kerr et al. provide the strongest direct support for the conformational-pivot
framing: a GIF-motif I-A mutation that enhances substrate binding
without impairing catalysis still attenuates the virus in vivo,
demonstrating that Mac1's conformational landscape (not just enzymatic
output) is critical for viral fitness. Stabilizing an unproductive
conformation could therefore achieve antiviral effects beyond what
active-site inhibition alone provides.
- reference: PMID:36598939
reference_title: "Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Overall, 160 ligands in 119 different scaffolds were discovered, and
153 Mac1-ligand complex crystal structures were determined, typically
to 1 Å resolution or better.
explanation: >-
Gahbauer et al. provide the largest crystallographic dataset for any
macrodomain. The diversity of scaffolds and the observed ligand-mediated
conformational changes establish Mac1 as a conformationally plastic
target amenable to allosteric and conformational-state-selective
chemistry.
- reference: PMID:36598939
reference_title: "Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our analyses discovered selective and cell-permeable molecules,
unexpected ligand-mediated conformational changes within the active site
explanation: >-
Observed conformational plasticity in response to diverse ligands
directly supports the assumption that Mac1 can be addressed by
conformational-state-selective chemistry, not only orthosteric
inhibition.
- reference: PMID:28991428
reference_title: "Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we identified a selective, allosteric and cell-active macrodomain
inhibitor, GeA-69, targeting macrodomain 2 of PARP14 in vitro and in
intact cells where it prevents its localisation to the sites of DNA
damage.
explanation: >-
Schuller et al. provide the validated allosteric precedent for any
macrodomain protein. GeA-69 binds outside the ADP-ribose pocket yet
blocks PARP14 MD2 function in cells, demonstrating that macrodomain
allosteric chemistry is feasible and can achieve selectivity
advantages over orthosteric approaches. This is the closest direct
precedent for the proposed Mac1 allosteric pivot strategy.
- reference: PMID:40736256
reference_title: "Mutations differentially affecting the coronavirus Mac1 ADP-ribose binding and hydrolysis activities indicate that it promotes multiple stages of the viral replication cycle."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Following infection, D1329A displayed a large defect in the accumulation
of viral RNA compared to WT or N1347A in all cells tested. Alternatively,
N1347A infection produced normal levels of viral RNA but produced reduced
levels of viral protein in interferon-competent bone marrow-derived
macrophages (BMDMs).
explanation: >-
In mouse hepatitis virus strain JHM, an adenine-binding mutation and a
hydrolysis mutation impair different stages of the replication cycle.
Mac1 is therefore not a single-activity enzyme whose output can be fully
described by catalytic rate, which is the substantive basis for treating
it as a conformational pivot rather than only as a hydrolase active
site.
- reference: PMID:30918076
reference_title: "Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Expression studies of the macrodomain-PLP2 portion of nsp3 indicate that
the ts mutations enhance proteasome-mediated degradation of the protein.
explanation: >-
Destabilizing the macrodomain routes the expressed macrodomain-PLP2
region of nsp3 into proteasomal degradation, which is the closest
published analogue of the degradation arm of this hypothesis. Two limits
on how far it can be carried: the work is in mouse hepatitis virus, and
the construct is a macrodomain-PLP2 fragment rather than full-length
nsp3, so it does not establish that a Mac1-directed warhead would degrade
the intact membrane-associated polyprotein.
- reference: PMID:39229055
reference_title: "Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does
not translate to demonstrable antiviral activity in cell culture and
iPSC-derived pneumocyte models
explanation: >-
Low-nanomolar orthosteric inhibitors engaged the target and raised
ADP-ribosylation without producing antiviral activity, including in
combination with interferon gamma. This is the strongest published case
that active-site occupancy alone may not be sufficient, which is the
premise the conformational-pivot framing rests on. Whether the null
result reflects the compounds or the assay system remains unsettled.
- reference: PMID:41258893
reference_title: "The Mac1 ADP-ribosylhydrolase is a therapeutic target for SARS-CoV-2."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral
replication, potentiates innate immune responses, and leads to a survival
benefit.
explanation: >-
Refutes the hypothesis's premise that broad antiviral effect is something
"active-site inhibition alone may not achieve". A conventional
ADP-ribose-pocket inhibitor delivers pharmacological proof of concept in
vivo, including a survival benefit. An allosteric or degradation-based
strategy must now demonstrate added value in breadth, resistance profile
or potency rather than merely working.
- reference: PMID:41565251
reference_title: "CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2."
supports: REFUTE
evidence_source: COMPUTATIONAL
snippet: "While active molecules discovered by CACHE #3 participants largely mimicked the adenine ring of the endogenous substrate, ADP-ribose, preserving the canonical chemotype commonly observed in previously reported Nsp3-Mac1 ligands"
explanation: "Refutes the specific sub-claim that the third CACHE challenge supplies a starting point for conformational-pivot chemistry. Twenty-three groups selecting 1739 candidates converged on canonical adenine-mimetic orthosteric ligands and produced no allosteric series, so CACHE #3 establishes target tractability without supplying the non-orthosteric chemical matter this hypothesis requires."
classifications:
harrisons_chapter:
- classification_value: INFECTIOUS_DISEASES
evidence:
- reference: PMID:32171076
reference_title: "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
coronavirus disease 2019 (COVID-19), caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)
explanation: >-
COVID-19 is an acute viral infectious disease caused by SARS-CoV-2,
placing it in Harrison's Infectious Diseases Part.
- classification_value: RESPIRATORY
evidence:
- reference: PMID:32109013
reference_title: "Clinical Characteristics of Coronavirus Disease 2019 in China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
On admission, ground-glass opacity was the most common radiologic
finding on chest computed tomography (CT) (56.4%).
explanation: >-
COVID-19 predominantly manifests as a lower-respiratory illness with
cough and pulmonary ground-glass opacities progressing to viral
pneumonia, aligning with Harrison's Respiratory Part.
pathophysiology:
- name: SARS-CoV-2 Spike-Mediated Entry via ACE2 and TMPRSS2
conforms_to: "host_directed_antiviral_dependency#Host Receptor and Protease Engagement"
description: >-
SARS-CoV-2 enters host cells via its spike (S) glycoprotein binding the
cellular receptor ACE2, followed by S protein priming by the host serine
protease TMPRSS2. ACE2 and TMPRSS2 co-expression on nasal, conducting
airway, and alveolar epithelial cells (particularly ciliated cells and
type II pneumocytes) defines the principal cellular tropism that drives
upper- and lower-respiratory disease.
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
- preferred_term: pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
genes:
- preferred_term: ACE2
term:
id: hgnc:13557
label: ACE2
- preferred_term: TMPRSS2
term:
id: hgnc:11876
label: TMPRSS2
evidence:
- reference: PMID:32142651
reference_title: "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry
and the serine protease TMPRSS2 for S protein priming
explanation: >-
Hoffmann et al. directly establish the ACE2 receptor and TMPRSS2-priming
entry mechanism that defines SARS-CoV-2 cell tropism.
downstream:
- target: SARS-CoV-2 Replicase Polyprotein Translation (pp1a/pp1ab)
description: >-
After spike-mediated entry and genome release, host translation produces
the pp1a and pp1ab replicase polyproteins.
- target: RNA Virus-Induced Interferon and PARP Activation
description: >-
Productive infection of airway and alveolar epithelium triggers the
host antiviral interferon program.
- target: Anosmia
description: >-
Infection of ACE2-expressing sustentacular support cells of the olfactory
epithelium disrupts olfactory function, producing loss of smell.
- target: Ageusia
description: >-
ACE2-mediated infection of oral/taste-associated epithelium contributes
to loss of taste.
- name: SARS-CoV-2 Replicase Polyprotein Translation (pp1a/pp1ab)
biological_scale: MOLECULAR
conforms_to: "viral_protease_inhibition#Synthesis of the Viral Polyprotein Precursor"
role: trigger
description: >-
Following entry and release of the positive-sense RNA genome, host
translational machinery produces the overlapping SARS-CoV-2 replicase
polyproteins pp1a and pp1ab. These precursors contain the nonstructural
proteins that must be released by PLpro and Mpro cleavage before the viral
replication machinery is functional.
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
- preferred_term: pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: Viral Gene Expression
term:
id: GO:0019080
label: viral gene expression
modifier: INCREASED
evidence:
- reference: PMID:35380892
reference_title: "Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
After viral entry, two overlapping polyproteins, pp1a (490 kDa) and pp1ab
(794 kDa), are translated by the translational machinery of the host.
explanation: >-
The structural study explicitly identifies host translation of pp1a and
pp1ab as the precursor-producing step after viral entry.
downstream:
- target: SARS-CoV-2 Mpro-Dependent Processing of pp1a/pp1ab
description: >-
Mpro cleaves defined junctions in pp1a and pp1ab to release replicase
nonstructural proteins.
- name: SARS-CoV-2 Mpro-Dependent Processing of pp1a/pp1ab
biological_scale: MOLECULAR
conforms_to: "viral_protease_inhibition#Virus-Encoded Protease-Dependent Polyprotein Processing"
role: therapeutic_vulnerability
description: >-
SARS-CoV-2 main protease (Mpro, also called 3CLpro or nsp5) is the viral
cysteine protease that cleaves at least 11 sites in the replicase
polyproteins pp1a and pp1ab. This releases nonstructural proteins needed for
the replication-transcription machinery. Mpro is distinct from the viral
papain-like protease PLpro, which performs other cleavage events.
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
- preferred_term: pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: Viral Protein Processing
term:
id: GO:0019082
label: viral protein processing
modifier: INCREASED
molecular_functions:
- preferred_term: Peptidase Activity
term:
id: GO:0008233
label: peptidase activity
evidence:
- reference: PMID:35380892
reference_title: "Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Mpro is a cysteine protease that cleaves at no less than 11 sites on the
replicase polyproteins
explanation: >-
The structural study directly defines Mpro's catalytic role and cleavage
burden on the SARS-CoV-2 replicase polyproteins.
- reference: PMID:35380892
reference_title: "Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the
nonstructural proteins (nsps)
explanation: >-
This directly supports release of nonstructural proteins as the output of
the Mpro processing step.
downstream:
- target: SARS-CoV-2 Replication-Transcription Complex Formation and RNA Replication
description: >-
Mpro-mediated processing releases functional nonstructural proteins that
support the replication-transcription complex and viral RNA replication.
- name: SARS-CoV-2 Replication-Transcription Complex Formation and RNA Replication
biological_scale: CELLULAR
conforms_to: "viral_protease_inhibition#Replication-Complex Formation and Viral RNA Replication"
role: effector
description: >-
Processed SARS-CoV-2 nonstructural proteins, including the RNA-dependent RNA
polymerase and helicase, form and support the replication-transcription
machinery that copies viral RNA. This is the replicase-branch output of
polyprotein processing and the downstream process interrupted by
nirmatrelvir inhibition of Mpro.
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
- preferred_term: pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: Viral RNA Genome Replication
term:
id: GO:0039694
label: viral RNA genome replication
modifier: INCREASED
evidence:
- reference: PMID:35380892
reference_title: "Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
replicase polyproteins essential for viral replication and transcription
explanation: >-
The study ties the Mpro-processed replicase polyproteins to viral
replication and transcription.
downstream:
- target: Enhanced Viral Replication and Tissue Pathology
description: >-
Replication-transcription complex activity increases viral burden in
respiratory epithelium, converging with viral immune evasion on tissue
injury and clinical disease.
- name: RNA Virus-Induced Interferon and PARP Activation
biological_scale: MOLECULAR
conforms_to: "parp_parg_macrodomain_viral_evasion#RNA Virus-Induced Interferon and PARP Activation"
description: >-
SARS-CoV-2 replication is sensed by pattern-recognition receptors that
induce type I and type III interferon signaling in infected respiratory
epithelium. Interferon signaling drives expression of PARP family members
(including PARP9 paired with the DTX3L E3 ligase) that catalyze antiviral
ADP-ribosylation as part of the innate antiviral program.
biological_processes:
- preferred_term: response to virus
term:
id: GO:0009615
label: response to virus
modifier: INCREASED
- preferred_term: positive regulation of defense response to virus by host
term:
id: GO:0002230
label: positive regulation of defense response to virus by host
modifier: INCREASED
evidence:
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
activation of the IFN response induces ADP-ribosylation of host proteins
explanation: >-
Russo et al. show that interferon-response activation drives host protein
ADP-ribosylation, instantiating the IFN-PARP arm of the macrodomain
module in human cells exposed to SARS-CoV-2 Nsp3.
downstream:
- target: Host PARP9/DTX3L Antiviral ADP-Ribosylation
description: >-
IFN-induced PARP9/DTX3L catalyzes mono-ADP-ribosylation of host substrates
as an antiviral effector.
- name: Host PARP9/DTX3L Antiviral ADP-Ribosylation
conforms_to: "parp_parg_macrodomain_viral_evasion#NAD-Dependent Antiviral ADP-Ribosylation"
description: >-
The interferon-inducible PARP9 ADP-ribosyltransferase, in complex with the
DTX3L E3 ligase, mono-ADP-ribosylates host proteins as a downstream effector
of the host antiviral interferon response. This NAD-dependent modification
is the substrate that the SARS-CoV-2 Nsp3 macrodomain targets and reverses.
genes:
- preferred_term: PARP9
term:
id: hgnc:24118
label: PARP9
- preferred_term: DTX3L
term:
id: hgnc:30323
label: DTX3L
biological_processes:
- preferred_term: protein poly-ADP-ribosylation
term:
id: GO:0070212
label: protein poly-ADP-ribosylation
modifier: INCREASED
evidence:
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This IFN-induced ADP-ribosylation is dependent on PARP9 and its binding
partner DTX3L
explanation: >-
Russo et al. identify PARP9/DTX3L as the IFN-dependent ADP-ribosylation
machinery whose product the Nsp3 macrodomain reverses.
downstream:
- target: Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
description: >-
The Nsp3 Mac1 macrodomain hydrolyzes the PARP9/DTX3L-deposited
mono-ADP-ribose marks on host proteins.
- name: Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
conforms_to: "parp_parg_macrodomain_viral_evasion#Viral Macrodomain De-ADP-Ribosylation Countermeasure"
description: >-
SARS-CoV-2 encodes a conserved macrodomain (Mac1) within nonstructural
protein 3 (Nsp3) that binds and hydrolyzes mono-ADP-ribose marks on host
proteins. Mac1 reverses the PARP9/DTX3L-dependent antiviral ADP-ribosylation
that the host interferon response deposits, neutralizing this branch of
innate immunity. The macrodomain is essential for coronavirus pathogenesis
in animal models and is the prototypical viral pivot point for this
mechanism module. Its conserved fold and druggable ADP-ribose pocket make
it an attractive target for both small-molecule inhibitors and
PROTAC-style degraders.
biological_processes:
- preferred_term: protein de-ADP-ribosylation
term:
id: GO:0051725
label: protein de-ADP-ribosylation
modifier: INCREASED
- preferred_term: negative regulation of defense response to virus by host
term:
id: GO:0050689
label: negative regulation of defense response to virus by host
modifier: INCREASED
evidence:
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All coronaviruses encode a highly conserved macrodomain (Mac1) that binds
to and removes ADP-ribose adducts from proteins
explanation: >-
Alhammad et al. directly establish that the SARS-CoV-2 Mac1 macrodomain
is a conserved ADP-ribose hydrolase, the defining viral countermeasure
enzyme.
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mac1 is essential for pathogenesis in multiple animal models of CoV
infection
explanation: >-
Mac1's essentiality across multiple in vivo coronavirus infection models
supports the macrodomain as the obligate viral pivot for ADP-ribosylation
countermeasure rather than an accessory function.
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ectopic expression of the SARS-CoV-2 Nsp3 macrodomain reverses this
modification in human cells
explanation: >-
Russo et al. directly demonstrate Nsp3 macrodomain-mediated reversal of
PARP9/DTX3L-deposited ADP-ribosylation in human cells.
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the cellular function of the SARS-CoV-2 Nsp3 macrodomain is to hydrolyze
this end product of IFN signaling, rather than to suppress the IFN
response itself
explanation: >-
The macrodomain acts at the effector level of the IFN antiviral program
(the ADP-ribosylated end product), not at upstream IFN signaling — the
interactome-rebalancing framing under which Mac1 is a precision pivot.
- reference: PMID:37607224
reference_title: "SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, in a mouse model of severe infection, ΔMac1 was quickly cleared
causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced
increased levels of interferon (IFN) and IFN-stimulated gene expression in
cell culture and mice, indicating that Mac1 blocks IFN responses which may
contribute to its attenuation.
explanation: >-
Reverse genetics in SARS-CoV-2 itself, rather than in a surrogate
coronavirus: complete deletion of the macrodomain leaves replication near
wild type in cell lines but abolishes pathogenesis in mice, with a
heightened interferon and interferon-stimulated gene response. This is
the direct genetic demonstration that the node's function is immune
counteraction rather than replication support.
- reference: PMID:41279050
reference_title: "Interactomics of SARS-CoV-2 Macrodomain 1 Reveals Putative Clients of ADP-ribosyl Hydrolase Activity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We identified interactions between Mac1 and ADP-ribosylated substrates
involved in DNA damage response, cytoskeletal components, and cell cycle
regulation.
explanation: >-
Affinity proteomics comparing wild-type Mac1 with the catalytically dead
N40D mutant places candidate ADP-ribosylated clients outside interferon
signaling, including TRiC chaperonin subunits in lung-derived A549 cells.
Two limits: the experiment transfects an isolated Strep-tagged Mac1
domain rather than infecting cells, and the paper presents these as
putative clients awaiting functional validation, so this widens the
candidate substrate set without redefining the node's established
interferon-directed function.
downstream:
- target: Enhanced Viral Replication and Tissue Pathology
description: >-
De-ADP-ribosylation of antiviral host substrates restores conditions
permissive for viral replication and downstream tissue damage.
- name: Enhanced Viral Replication and Tissue Pathology
biological_scale: TISSUE
conforms_to: "parp_parg_macrodomain_viral_evasion#Enhanced Viral Replication and Pathogenesis"
description: >-
By neutralizing host PARP9/DTX3L-dependent antiviral ADP-ribosylation, the
Nsp3 macrodomain permits sustained viral replication in respiratory
epithelium, leading to alveolar epithelial injury, diffuse alveolar damage,
and recruitment of innate immune effectors. The interplay of viral
cytopathic injury and dysregulated host responses drives the pneumonia,
hypoxemia, and acute respiratory distress syndrome that characterize severe
COVID-19.
biological_processes:
- preferred_term: viral life cycle
term:
id: GO:0019058
label: viral life cycle
modifier: INCREASED
evidence:
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The macrodomain is essential for CoV pathogenesis and may be a novel
therapeutic target.
explanation: >-
Macrodomain essentiality for coronavirus pathogenesis links the Mac1
activity directly to viral replication and tissue pathology in vivo.
downstream:
- target: Cytokine-Driven Acute Respiratory Distress Syndrome
description: >-
Severe disease is marked by dysregulated cytokine responses and diffuse
alveolar damage.
- target: Endothelial Injury and Prothrombotic Coagulopathy
hypothesis_groups:
- endotheliopathy_centred_pathophysiology_model
description: >-
SARS-CoV-2-driven injury of vascular endothelium activates coagulation and
thrombo-inflammation beyond the respiratory epithelial compartment.
- target: Pneumonia
description: >-
Viral replication and inflammatory injury of the lower respiratory tract
produce viral pneumonia.
- target: Cough
description: >-
Infection and inflammation of the airway epithelium stimulate the cough
reflex.
- target: Dyspnea
description: >-
Alveolar and interstitial lung injury impairs gas exchange, producing
breathlessness.
- name: Cytokine-Driven Acute Respiratory Distress Syndrome
description: >-
A subset of patients develops severe lower-respiratory disease with
elevated inflammatory cytokines, lymphopenia, diffuse alveolar damage, and
acute respiratory distress syndrome (ARDS). Markedly elevated IL-6 and
other inflammatory mediators identify a hyperinflammatory state amenable
to corticosteroid and anti-cytokine therapy.
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: INCREASED
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Compared with non-ICU patients, ICU patients had higher plasma levels of
IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
explanation: >-
Huang et al. directly document the hyperinflammatory cytokine profile
that distinguishes severe ICU-level COVID-19 from milder disease.
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complications included acute respiratory distress syndrome
explanation: >-
The Wuhan cohort directly links severe COVID-19 to ARDS as the dominant
lethal complication.
downstream:
- target: Acute Respiratory Distress Syndrome
description: >-
The hyperinflammatory cytokine state with diffuse alveolar damage
culminates in clinical acute respiratory distress syndrome.
- target: Fever
description: >-
Pyrogenic cytokines (IL-1, IL-6, TNF-α) elevated during the cytokine
storm raise the hypothalamic set-point, producing fever.
- target: Lymphopenia
description: >-
Cytokine-driven lymphocyte apoptosis and tissue redistribution contribute
to the lymphopenia characteristic of acute COVID-19.
- name: Endothelial Injury and Prothrombotic Coagulopathy
description: >-
Beyond direct respiratory epithelial injury, severe COVID-19 is
characterized by endothelial activation and a prothrombotic coagulopathy.
SARS-CoV-2-driven immuno-inflammatory and endothelial derangements promote
micro- and macro-vascular thrombosis — reflected clinically in elevated
D-dimer — and contribute to the multi-organ dysfunction that defines the
lethal disease phenotype. This node instantiates the emerging
endotheliopathy-centred pathophysiology model at the tissue scale, parallel
to the cellular macrodomain immune-evasion arm.
biological_processes:
- preferred_term: blood coagulation
term:
id: GO:0007596
label: blood coagulation
modifier: INCREASED
evidence:
- reference: PMID:33965003
reference_title: "The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Such complex manifestations suggest that SARS-CoV-2 dysregulates the
host response, triggering wide-ranging immuno-inflammatory, thrombotic,
and parenchymal derangements.
explanation: >-
Osuchowski et al. frame severe COVID-19 as a host-response dysregulation
producing immuno-inflammatory and thrombotic derangements — the
endotheliopathy-centred pathophysiology this node captures.
- reference: PMID:32171076
reference_title: "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033)
explanation: >-
Admission D-dimer greater than 1 μg/mL is a strong independent mortality
risk factor, the clinical readout of the prothrombotic coagulopathy
modeled by this node.
- reference: PMID:42340782
reference_title: "Comprehensive Evaluation of Coronary Pathophysiology in the Context of COVID-19: Clinical Insights and Angiographic Assessment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the COVID-19 group had higher smoking rates, STEMI (50% vs. 26.3%), and
elevated D-dimer, C reactive protein (CRP), and cardiac troponins. COVID-19
patients had more ventricular thrombus (15% vs. 3.75%), RV dilation
(36.25% vs. 11.25%), and pulmonary hypertension (50% vs. 26.3%)
explanation: >-
Riyadh (King Saud Medical City) case-control angiographic study directly demonstrates COVID-19-driven
prothrombotic coagulopathy with cardiac-specific manifestations: elevated
D-dimer, ventricular thrombus, and elevated troponins document endothelial
injury and thrombotic complications; pulmonary hypertension and RV dilation
extend the endotheliopathy model to pulmonary vasculature.
downstream:
- target: Elevated D-dimer
hypothesis_groups:
- endotheliopathy_centred_pathophysiology_model
description: >-
Endothelial injury and activation of coagulation elevate circulating
D-dimer, a marker of the COVID-19 coagulopathy.
phenotypes:
- category: Constitutional
name: Fever
frequency: VERY_FREQUENT
description: >-
Fever is the dominant presenting symptom of acute COVID-19 and was reported
in 98% of hospitalized patients in the initial Wuhan cohort.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Common symptoms at onset of illness were fever
explanation: >-
The Wuhan cohort directly documents fever as the dominant presenting
symptom of acute COVID-19.
- category: Respiratory
name: Cough
frequency: FREQUENT
description: >-
Cough is among the most common presenting symptoms of acute COVID-19.
phenotype_term:
preferred_term: Cough
term:
id: HP:0012735
label: Cough
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
of 41 patients), cough
explanation: >-
Huang et al. directly enumerate cough among the most common presenting
symptoms (76% of patients) in the initial Wuhan hospitalized cohort.
- category: Respiratory
name: Dyspnea
frequency: FREQUENT
description: >-
Dyspnea typically develops several days after symptom onset and marks
progression from upper-respiratory illness to viral pneumonia.
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dyspnoea developed in
explanation: >-
Dyspnea is one of the cardinal clinical features documented in the
initial Wuhan hospitalized cohort, with median onset around day 8 from
symptom onset.
- category: Respiratory
name: Pneumonia
frequency: VERY_FREQUENT
description: >-
Bilateral viral pneumonia with ground-glass opacities on chest imaging is
the canonical lower-respiratory manifestation of moderate-to-severe acute
COVID-19.
phenotype_term:
preferred_term: Pneumonia
term:
id: HP:0002090
label: Pneumonia
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All 41 patients had pneumonia with abnormal findings on chest CT.
explanation: >-
Pneumonia with chest CT abnormalities was universal in the initial
hospitalized cohort.
- category: Respiratory
name: Acute Respiratory Distress Syndrome
frequency: OCCASIONAL
description: >-
A subset of patients with severe COVID-19 develop hypoxemic respiratory
failure meeting Berlin ARDS criteria, requiring high-flow oxygen,
non-invasive ventilation, or mechanical ventilation.
phenotype_term:
preferred_term: Acute respiratory distress syndrome
term:
id: HP:0033677
label: Acute respiratory distress syndrome
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complications included acute respiratory distress syndrome
explanation: >-
ARDS was a documented complication in the initial Wuhan hospitalized
cohort.
- category: Neurologic
name: Anosmia
frequency: FREQUENT
description: >-
Sudden-onset loss of smell, often accompanied by loss of taste, is highly
associated with SARS-CoV-2 infection and is the single strongest symptom
predictor of a positive test in community cohorts.
phenotype_term:
preferred_term: Anosmia
term:
id: HP:0000458
label: Anosmia
evidence:
- reference: PMID:32393804
reference_title: "Real-time tracking of self-reported symptoms to predict potential COVID-19."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the proportion of participants who reported loss of smell and taste was
higher in those with a positive test result (4,668 of 7,178 individuals;
65.03%) than in those with a negative test result (2,436 of 11,223
participants; 21.71%) (odds ratio = 6.74; 95% confidence interval =
6.31-7.21)
explanation: >-
The Menni et al. symptom-tracker cohort (2.6 million participants)
directly establishes loss of smell and taste as the single strongest
discriminating symptom of SARS-CoV-2 infection: reported by 65% of
test-positive versus 22% of test-negative participants (adjusted
meta-analytic odds ratio 6.74).
- category: Neurologic
name: Ageusia
frequency: FREQUENT
description: >-
Loss of taste commonly co-occurs with anosmia in acute COVID-19.
phenotype_term:
preferred_term: Ageusia
term:
id: HP:0041051
label: Ageusia
evidence:
- reference: PMID:32393804
reference_title: "Real-time tracking of self-reported symptoms to predict potential COVID-19."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the proportion of participants who reported loss of smell and taste was
higher in those with a positive test result
explanation: >-
Loss of taste was reported together with loss of smell in the Menni
symptom-tracker cohort as a discriminating COVID-19 symptom.
- category: Laboratory Abnormality
name: Lymphopenia
frequency: FREQUENT
description: >-
Reduced peripheral lymphocyte counts are commonly observed in moderate-
to-severe COVID-19 and track with disease severity.
phenotype_term:
preferred_term: Infection-associated lymphopenia
term:
id: HP:4000034
label: Infection-associated lymphopenia
evidence:
- reference: PMID:31986264
reference_title: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
of 41 patients had lymphopenia
explanation: >-
Lymphopenia was reported as a common laboratory finding in the initial
hospitalized cohort.
- category: Laboratory Abnormality
name: Elevated D-dimer
description: >-
Elevated circulating D-dimer, reflecting the prothrombotic coagulopathy of
COVID-19, is a strong independent predictor of in-hospital mortality. In the
Wuhan inpatient cohort, admission D-dimer greater than 1 μg/mL carried an
18-fold increase in the odds of death.
phenotype_term:
preferred_term: Elevated circulating D-dimer concentration
term:
id: HP:0033106
label: Elevated circulating D-dimer concentration
evidence:
- reference: PMID:32171076
reference_title: "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
increasing odds of in-hospital death associated with older age (odds
ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher
Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23;
p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033)
on admission
explanation: >-
Zhou et al. identify admission D-dimer greater than 1 μg/mL as a strong
independent risk factor for COVID-19 in-hospital death, documenting the
elevated D-dimer that marks the prothrombotic coagulopathy of severe acute
COVID-19.
genetic:
- name: ACE2
association: Host receptor susceptibility
gene_term:
preferred_term: ACE2
term:
id: hgnc:13557
label: ACE2
notes: >-
ACE2 is the cellular receptor used by the SARS-CoV-2 spike glycoprotein for
cell entry. Genetic variation in ACE2 expression and inter-individual
differences in ACE2 distribution across airway and alveolar epithelium
contribute to susceptibility and disease severity.
evidence:
- reference: PMID:32142651
reference_title: "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry
and the serine protease TMPRSS2 for S protein priming
explanation: >-
Hoffmann et al. establish ACE2 as the obligate SARS-CoV-2 entry receptor.
- name: TMPRSS2
association: Host protease cofactor
gene_term:
preferred_term: TMPRSS2
term:
id: hgnc:11876
label: TMPRSS2
notes: >-
TMPRSS2 is the principal host serine protease that primes the SARS-CoV-2
spike protein for membrane fusion. Pharmacologic inhibition of TMPRSS2
blocks viral entry in cell culture and is a validated host-directed
antiviral strategy.
evidence:
- reference: PMID:32142651
reference_title: "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
A TMPRSS2 inhibitor approved for clinical use blocked entry and might
constitute a treatment option
explanation: >-
TMPRSS2 priming is a druggable host-directed step in SARS-CoV-2 entry.
diagnosis:
- name: SARS-CoV-2 nucleic acid amplification test
description: >-
Detection of SARS-CoV-2 RNA by a nucleic acid amplification test (NAAT),
usually RT-PCR, on an upper respiratory specimen. It is the test the IDSA
recommends for every symptomatic person suspected of having COVID-19, and
it is suggested for asymptomatic contacts when the result will change
isolation, quarantine or protective-equipment decisions.
measurements:
- preferred_term: SARS-CoV-2 RNA
term:
id: LOINC:105909-6
label: SARS-CoV-2 (COVID-19) RNA [Presence] in Specimen
notes: >-
The method-less qualitative code with an unspecified specimen is bound,
rather than one of the many nasopharyngeal, saliva or respiratory-specimen
variants by probe or non-probe NAA, because the guideline accepts
several upper respiratory specimens and both rapid and laboratory-based
NAAT. No reference_ranges are recorded. The IDSA panel found the data
insufficient to judge infectiousness from cycle threshold values, which
are instrument signals specific to each assay, so the cycle-threshold
codes are not bound and no Ct band is recorded.
evidence:
- reference: PMID:38112284
reference_title: "The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing (December 2023)."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
the IDSA panel weighed available diagnostic evidence and recommends
nucleic acid testing for all symptomatic individuals suspected of
having COVID-19
explanation: >-
IDSA guideline recommending nucleic acid testing for all symptomatic
individuals suspected of COVID-19. Evidence source is OTHER as this is
a practice guideline.
- reference: PMID:38112284
reference_title: "The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing (December 2023)."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The IDSA panel concluded that data were insufficient to establish
SARS-CoV-2 infectiousness of a patient based on nonstandardized
instrument signal values, such as cycle threshold (Ct) values.
explanation: >-
The guideline declines to interpret Ct values, which is why no Ct band
is recorded on the NAAT measurement. Evidence source is OTHER as this
is a practice guideline.
- name: SARS-CoV-2 antigen test
description: >-
Immunoassay detection of SARS-CoV-2 protein antigen, most often as a
point-of-care lateral flow test. Antigen tests are highly specific but
less sensitive than NAAT, so NAAT remains the test of choice; antigen
testing is used when timely molecular testing is not available, and a
positive result can in most cases be acted on without confirmation.
measurements:
- preferred_term: SARS-CoV-2 antigen
term:
id: LOINC:105066-5
label: SARS-CoV+SARS-CoV-2 (COVID-19) Ag [Presence] in Specimen
notes: >-
The bound code is the method-less qualitative antigen code with an
unspecified specimen. Its component names SARS-CoV and SARS-CoV-2
together, which is how LOINC codes these antigen assays. A query of the
Monarch KG LOINC nodes for antigen-presence codes naming SARS-CoV-2 found
no method-less code naming SARS-CoV-2 alone; the SARS-CoV-2-only antigen
codes it returned are each specific to a method (rapid immunoassay,
immunoassay or immunofluorescence) and to a respiratory specimen (for
example LOINC:94558-4 SARS-CoV-2
(COVID-19) Ag [Presence] in Respiratory system specimen by Rapid
immunoassay). The result is qualitative and no reference_ranges are
recorded.
evidence:
- reference: PMID:36702617
reference_title: "The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing (January 2023)."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
US Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency
Use Authorization (EUA) have high specificity and low to moderate
sensitivity compared with nucleic acid amplification testing (NAAT).
explanation: >-
IDSA guideline comparing antigen tests with NAAT. Evidence source is
OTHER as this is a practice guideline.
- reference: PMID:36702617
reference_title: "The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing (January 2023)."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
However, when timely molecular testing is not readily available or is
logistically infeasible, Ag testing helps identify individuals with
SARS-CoV-2 infection.
explanation: >-
Places antigen testing after NAAT, for when molecular testing is not
available in time. Evidence source is OTHER as this is a practice
guideline.
- reference: PMID:36702617
reference_title: "The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Antigen Testing (January 2023)."
supports: SUPPORT
evidence_source: OTHER
snippet: In most cases, positive Ag results can be acted upon without confirmation.
explanation: >-
A positive antigen result usually needs no confirmatory test. Evidence
source is OTHER as this is a practice guideline.
- name: SARS-CoV-2 antibody serology
description: >-
Detection of antibody to SARS-CoV-2. Serology is not used to diagnose
acute infection in the first two weeks after symptom onset. Antibody to
the nucleocapsid protein, tested three to five weeks after symptom onset,
is the suggested evidence of prior infection. Routine serology is not
suggested after previous infection or vaccination, but a negative spike
antibody result may identify immunocompromised patients who are
candidates for immune therapy.
measurements:
- preferred_term: SARS-CoV-2 anti-nucleocapsid IgG
term:
id: LOINC:99596-9
label: SARS-CoV-2 (COVID-19) N protein IgG Ab [Presence] in Serum or Plasma by Immunoassay
- preferred_term: SARS-CoV-2 anti-spike IgG
term:
id: LOINC:99597-7
label: SARS-CoV-2 (COVID-19) S protein IgG Ab [Presence] in Serum or Plasma by Immunoassay
notes: >-
Anti-nucleocapsid and anti-spike antibody are two assays with different
clinical uses, so they are two measurements. A query of the Monarch KG
LOINC nodes for antibody codes naming the N or S protein of SARS-CoV-2
returned only these immunoassay codes and spike receptor-binding-domain
neutralizing-antibody codes, with no method-less N- or S-protein antibody
code; immunoassay is a method class covering ELISA and chemiluminescent
formats rather than a single kit. The guideline also accepts IgG/IgM or
total anti-nucleocapsid antibody, which these IgG codes do not name. No
reference_ranges are recorded: the guideline abstract (the only text of
PMID:38489670 in references_cache) states no antibody concentration
threshold, and says future studies should use assays calibrated to a
common reference standard.
evidence:
- reference: PMID:38489670
reference_title: "Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The panel recommends against serologic testing to diagnose SARS-CoV-2
infection in the first two weeks after symptom onset
explanation: >-
IDSA guideline excluding serology from diagnosis of acute infection.
Evidence source is OTHER as this is a practice guideline.
- reference: PMID:38489670
reference_title: "Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
To seek evidence for prior SARS-CoV-2 infection, the panel suggests
testing for IgG, IgG/IgM, or total antibodies to nucleocapsid protein
three to five weeks after symptom onset
explanation: >-
Names anti-nucleocapsid antibody as the serologic marker of prior
infection. Evidence source is OTHER as this is a practice guideline.
- reference: PMID:38489670
reference_title: "Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The panel acknowledges further that a negative spike antibody test may
be a useful metric to identify immunocompromised patients who are
candidates for immune therapy.
explanation: >-
Names the spike antibody test and its use in immunocompromised
patients. Evidence source is OTHER as this is a practice guideline.
- reference: PMID:38489670
reference_title: "Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In individuals with previous SARS-CoV-2 infection or vaccination, we
suggest against routine serologic testing given no demonstrated benefit
to improving patient outcomes
explanation: >-
The guideline suggests against routine serology after infection or
vaccination. Evidence source is OTHER as this is a practice guideline.
treatments:
- name: Nirmatrelvir/Ritonavir (Paxlovid)
description: >-
Oral nirmatrelvir directly inhibits SARS-CoV-2 main protease
(Mpro/3CLpro), while ritonavir inhibits host CYP3A to increase nirmatrelvir
exposure rather than serving as a second SARS-CoV-2 protease inhibitor.
The regimen is recommended for outpatients with mild-to-moderate COVID-19
at high risk of progression to severe disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: nirmatrelvir
term:
id: CHEBI:170007
label: nirmatrelvir
- preferred_term: ritonavir
term:
id: CHEBI:45409
label: ritonavir
target_mechanisms:
- target: SARS-CoV-2 Mpro-Dependent Processing of pp1a/pp1ab
treatment_effect: INHIBITS
description: >-
The nirmatrelvir component directly inhibits SARS-CoV-2 Mpro and thereby
blocks Mpro-dependent processing of pp1a and pp1ab. Ritonavir's role in
this regimen is pharmacokinetic enhancement through host CYP3A
inhibition, separate from this viral target edge.
evidence:
- reference: PMID:34726479
reference_title: "An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
discovery and characterization of PF-07321332, an orally bioavailable
SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus
antiviral activity
explanation: >-
PF-07321332 is nirmatrelvir; the primary discovery study directly
identifies it as a SARS-CoV-2 main-protease inhibitor with antiviral
activity.
evidence:
- reference: PMID:41920902
reference_title: "2025 Clinical Practice Guideline Update by the Infectious Diseases Society of America on the Treatment and Management of COVID-19: Antiviral Treatment for Mild to Moderate COVID-19 in Adults."
supports: SUPPORT
evidence_source: OTHER
snippet: "The guideline panel presents 9 updated recommendations on the use of nirmatrelvir/ritonavir, remdesivir, and molnupiravir, in adults with mild to moderate COVID-19."
explanation: The 2025 IDSA guideline update recommends nirmatrelvir/ritonavir among the antivirals for mild-to-moderate COVID-19 in adults.
- name: Remdesivir
description: >-
Intravenous nucleotide-analog inhibitor of the SARS-CoV-2 RNA-dependent
RNA polymerase, used in hospitalized patients with COVID-19 requiring
supplemental oxygen.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: remdesivir
term:
id: CHEBI:145994
label: remdesivir
evidence:
- reference: PMID:41920902
reference_title: "2025 Clinical Practice Guideline Update by the Infectious Diseases Society of America on the Treatment and Management of COVID-19: Antiviral Treatment for Mild to Moderate COVID-19 in Adults."
supports: SUPPORT
evidence_source: OTHER
snippet: "The guideline panel presents 9 updated recommendations on the use of nirmatrelvir/ritonavir, remdesivir, and molnupiravir, in adults with mild to moderate COVID-19."
explanation: The 2025 IDSA guideline update includes remdesivir among the recommended antivirals for mild-to-moderate COVID-19.
- name: Dexamethasone
description: >-
Systemic corticosteroid that reduces mortality in patients with COVID-19
requiring supplemental oxygen or mechanical ventilation by suppressing the
hyperinflammatory host response.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: dexamethasone
term:
id: CHEBI:41879
label: dexamethasone
- name: COVID-19 Vaccination
description: >-
Active immunization against the SARS-CoV-2 spike protein (mRNA, adenoviral
vector, recombinant protein, and inactivated platforms) is the principal
population-level intervention against COVID-19 and reduces severe disease
and death.
therapeutic_modality: VACCINE
treatment_term:
preferred_term: vaccination
term:
id: NCIT:C15346
label: Vaccination
- name: Peginterferon Lambda
description: >-
Pegylated interferon lambda-1A is an innate-immunity-modulator (a type III
interferon) that pharmacologically augments the host interferon-stimulated
antiviral state. In the TOGETHER randomized trial, a single subcutaneous dose
given early to outpatients significantly reduced COVID-19 hospitalization or
emergency-department visits, with benefit consistent across SARS-CoV-2
variants — the broad-spectrum, host-directed signature of an interferon-based
antiviral.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: peginterferon lambda-1A
term:
id: NCIT:C166435
label: Peginterferon Lambda-1A
target_mechanisms:
- target: RNA Virus-Induced Interferon and PARP Activation
treatment_effect: ACTIVATES
description: >-
Peginterferon lambda supplies exogenous type III interferon that reinforces
the host interferon-stimulated antiviral program this node initiates,
restricting viral replication; it conceptually counters the viral macrodomain
countermeasure that degrades the downstream ADP-ribosylation output.
evidence:
- reference: PMID:36780676
reference_title: "Early Treatment with Pegylated Interferon Lambda for Covid-19."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among predominantly vaccinated outpatients with Covid-19, the incidence of
hospitalization or an emergency department visit (observation for >6 hours)
was significantly lower among those who received a single dose of pegylated
interferon lambda than among those who received placebo.
explanation: >-
Randomized-trial evidence that augmenting the interferon response with
peginterferon lambda restricts COVID-19, supporting this treatment's action
on the interferon node. Evidence source is HUMAN_CLINICAL as this is a
randomized controlled trial.
computational_models:
- name: COVID-19 Disease Map SBML-qual Boolean Models
description: >-
Executable Boolean networks generated from the COVID-19 Disease Map (C19DMap), the
community-curated repository of SARS-CoV-2 virus-host mechanism diagrams. The
CellDesigner diagrams were translated to SBML-qual with CaSQ, retaining the source
diagrams' references, annotations and layout, and deposited on FAIRDOMHub as a
reusable model collection. Because the translation is automated and layout-aware,
each Boolean model remains traceable back to the curated diagram and the literature
behind it — the property that makes the collection reviewable rather than opaque.
model_type: BOOLEAN_NETWORK
model_format: SBML-qual
model_software: CaSQ, CellDesigner
repository_url: https://fairdomhub.org/models/714
publication: PMID:34664389
modeled_mechanisms:
- target: RNA Virus-Induced Interferon and PARP Activation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
divergences:
- divergence_type: CALIBRATION_PROVENANCE
materiality: QUALIFYING
description: >-
CaSQ infers update rules from the CellDesigner diagram's topology and
semantic annotations. No kinetic parameterisation is performed and no
fitting to interferon-response data is involved, so the model inherits
whatever the curated diagram asserts.
- divergence_type: TEMPORAL_SCOPE
materiality: QUALIFYING
description: >-
The models establish qualitative reachability of the interferon response,
not its magnitude or timing -- both of which are central to whether the
response controls SARS-CoV-2 or contributes to immunopathology.
description: >-
Interferon-signalling diagrams are among the C19DMap content translated into
discrete models, making the host interferon response simulable rather than only
browsable.
limitations: >-
CaSQ infers rules from diagram topology and semantics without kinetic
parameterisation, so the models capture qualitative reachability of the interferon
response rather than its magnitude or timing.
evidence:
- reference: PMID:34664389
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
C19DMap diagrams, translated to SBML qual using CaSQ (see Materials and
Methods), can be used in discrete modelling, using modelling software that
supports SBML qual file import
explanation: >-
Establishes that the curated diagrams underlying this node are available as
executable discrete models.
findings:
- statement: >-
The generated SBML-qual files retain the references, annotations and layout of the
source CellDesigner diagrams, so each Boolean model stays traceable to its
curation.
evidence:
- reference: PMID:34664389
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
SBML‐qual files (Chaouiya et al, 2013) generated with CaSQ (Aghamiri et al,
2020) retained their references, annotations and layout of the original
CellDesigner file
explanation: >-
Documents the provenance-preserving property of the map-to-model translation.
evidence:
- reference: PMID:34664389
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
The C19DMap diagrams are available in several layout‐aware systems biology formats
and integrated with external repositories, allowing a range of computational
analyses, including network analysis and Boolean, kinetic or multiscale
simulations
explanation: >-
Establishes Boolean simulation as a supported analysis of the COVID-19 Disease Map
content.
notes: >-
Curated as part of the Boolean/logical modelling track; see
docs/superpowers/plans/2026-08-28-boolean-modeling-and-pathographs.md. A collection
rather than a single network — FAIRDOMHub model 714 holds SBML-qual translations of
selected C19DMap diagrams. Literature-referenced, not runnable in-repo.
- name: Type 1 Interferon Signalling Boolean Model
description: >-
An executable, dynamic Boolean model of type 1 interferon signalling derived from
the COVID-19 Disease Map interferon diagram using CaSQ and the same map-to-model
framework as the rheumatoid arthritis FLS model. Simulated in Cell Collective under
virus infection, inflammatory conditions, and both combined, it yields 128 stable
states and no oscillations, which are clustered by four output nodes — viral
replication, antiviral response, inflammation, and IFNA1 secretion. Systematic
single-node knockouts across this and companion apoptosis and macrophage models were
used to nominate drug targets.
model_type: BOOLEAN_NETWORK
model_format: SBML-qual
model_software: CaSQ, Cell Collective
repository_url: https://git-r3lab.uni.lu/covid/models
publication: PMID:38414974
modeled_mechanisms:
- target: RNA Virus-Induced Interferon and PARP Activation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
divergences:
- divergence_type: TEMPORAL_SCOPE
materiality: QUALIFYING
description: >-
Analysis is of stable states: 128 of them, with no oscillations. That
characterises where the network settles, not the kinetics of interferon
induction, which is what distinguishes an early controlling response from
a late damaging one.
- divergence_type: CALIBRATION_PROVENANCE
materiality: QUALIFYING
description: >-
Auto-generated by CaSQ from the disease-map interferon diagram; the
sensitivity analysis varies input activity levels in Cell Collective
rather than fitting the model to measured interferon responses.
description: >-
The model encodes the type 1 interferon cascade and the points at which SARS-CoV-2
proteins interrupt it, with antiviral response and IFNA1 secretion as two of its
four output nodes.
readouts:
- name: Antiviral response and IFNA1 secretion output nodes
target: RNA Virus-Induced Interferon and PARP Activation
direction: ALTERED
interpretation: >-
Stable states are clustered by the four output nodes; the antiviral-response and
IFNA1 clusters distinguish an intact interferon response from a virus-blocked one.
evidence:
- reference: PMID:38414974
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
We then clustered the stable states according to the four outputs of interest:
viral replication, antiviral response, inflammation, and secretion of IFNA1
explanation: >-
Names the model's phenotype-level output nodes, which are the readouts for
this link.
evidence:
- reference: PMID:38414974
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
We used the tool CaSQ and a previously described map-to-model translation
framework (33) to obtain an executable, dynamic Boolean model of type 1 IFN
signalling
explanation: >-
Establishes the model's subject and its derivation from the disease map.
- target: Enhanced Viral Replication and Tissue Pathology
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: MOLECULAR
divergences:
- divergence_type: PROXY_QUANTITY
materiality: INVALIDATING
description: >-
Viral replication here is one of four Boolean output nodes used to cluster
stable states of a host-signalling network. It indexes whether host
restriction is relieved; it is not viral titre, and nothing in the model
reports alveolar epithelial injury or diffuse alveolar damage.
- divergence_type: SCALE_EXTRAPOLATION
materiality: QUALIFYING
description: >-
Two scale steps from a molecular signalling network to tissue pathology.
- divergence_type: BOUNDARY_OMISSION
materiality: QUALIFYING
description: >-
Tissue-scale consequences are reached only when the companion epithelial
apoptosis and macrophage models are embedded in a separate multiscale
lung-infection simulator, which is outside this model.
- divergence_type: TEMPORAL_SCOPE
materiality: QUALIFYING
description: >-
No replication kinetics; stable states carry no time course.
description: >-
Viral replication is one of the four output nodes used to cluster stable states,
and the model represents virus-mediated blockade of interferon signalling at
several cascade levels.
limitations: >-
Viral replication is a Boolean output node of a host-signalling network, not a
model of replication kinetics or of tissue-level pathology; the companion
epithelial-apoptosis and macrophage models reach tissue scale only when embedded in
a separate multiscale simulator.
evidence:
- reference: PMID:38414974
supports: SUPPORT
directness: INDIRECT
evidence_source: COMPUTATIONAL
snippet: >-
The virus can also block the type 1 IFN signalling at different cascade levels,
as demonstrated in the molecular-level model
explanation: >-
Supports the interferon-evasion mechanism that raises viral replication in the
model. Indirect for this node: the quote asserts molecular-level blockade of
interferon signalling, and tissue pathology follows only by an inference step,
which is also why fidelity here is LOW.
findings:
- statement: >-
The model yields 128 stable states and no oscillations, clustered by four output
nodes.
evidence:
- reference: PMID:38414974
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: We could identify 128 stable states and no oscillations using this modified model
explanation: Reports the attractor analysis result for this model.
- statement: >-
Single-node knockouts of each Boolean model were used to nominate candidate drug
targets.
evidence:
- reference: PMID:38414974
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Models were analysed individually by studying each Boolean model’s knockout (KO)
(46) to identify potential drug targets
explanation: >-
Documents the in-silico perturbation strategy used for target identification.
notes: >-
Curated as part of the Boolean/logical modelling track; see
docs/superpowers/plans/2026-08-28-boolean-modeling-and-pathographs.md. Two companion
Boolean models from the same work — respiratory epithelium apoptosis and macrophage
immune-cell recruitment — were embedded in a multiscale lung-infection simulator; they
are not separately curated here. Literature-referenced, not runnable in-repo.
discussions:
- discussion_id: gap_covid_acute_vs_persistent_diabetes
prompt: >-
What distinguishes acute hyperglycemia during COVID-19 hospitalization
(stress-hyperglycemia) from persistent de novo diabetes development
post-COVID? Do the pathways driving acute metabolic decompensation during
infection differ mechanistically from those driving long-term beta-cell
loss or insulin resistance post-infection?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#SARS-CoV-2 Spike-Mediated Entry via ACE2 and TMPRSS2
rationale: >-
COVID-19 hospitalized patients frequently develop hyperglycemia (~50%),
but the majority resolve it post-discharge. However, population cohort
studies (OpenSAFELY, N3C) and registry data report incident diabetes cases
years post-infection. The mechanism(s) linking acute infection-driven
hyperglycemia to persistent diabetes risk is not clear: stress-hyperglycemia
may unmask pre-existing insulin resistance that progresses to type 2
diabetes, acute direct infection of beta cells may cause lasting damage,
or unresolved post-viral inflammation may sustain pathways months/years
later. A prospective multi-timepoint mechanistic study is needed.
evidence:
- reference: PMID:42362970
reference_title: "SARS-CoV-2 and diabetes: a post-pandemic reappraisal."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
stress- and treatment-induced hyperglycaemia is common in critical
illness, occurring in approximately 50% of affected individuals. While
often transient, these effects may unmask persistent metabolic
dysfunction in individuals at risk of type 2 diabetes [36, 37].
explanation: >-
Identifies the unresolved distinction: acute hyperglycemia may be
reversible stress-response versus a marker of persistent damage.
- discussion_id: gap_covid_type1_vs_type2_divergence
prompt: >-
SARS-CoV-2 infection has been associated with both incident type 1 and
type 2 diabetes, yet the mechanistic pathways and patient risk factors
that predispose to one versus the other remain unclear. Do viral and/or
host immune and metabolic pathways distinguish type 1 (autoimmune
beta-cell destruction) from type 2 (insulin resistance + relative
beta-cell inadequacy) post-COVID trajectories?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#SARS-CoV-2 Spike-Mediated Entry via ACE2 and TMPRSS2
rationale: >-
Meta-analyses and prospective cohorts report increased incidence of both
type 1 diabetes (especially in children with new-onset DKA above baseline)
and type 2 diabetes (particularly in hospitalized and older adults). The
role of SARS-CoV-2 as a direct trigger of autoimmunity, a driver of
insulin resistance through persistent inflammation, or an unmasker of
pre-existing glucose intolerance is not yet resolved. Mechanistic and
genetic factors that predict which type develops are largely unknown.
evidence:
- reference: PMID:42362970
reference_title: "SARS-CoV-2 and diabetes: a post-pandemic reappraisal."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Soon, additional studies began to identify similar increases in new-onset
type 2 diabetes [17].
explanation: >-
Documents both type 1 and type 2 incidence increases post-COVID, raising
the question of shared versus divergent mechanisms.
- discussion_id: gap_covid_macrodomain_allosteric_pivot
prompt: >-
Can the SARS-CoV-2 Nsp3 Mac1 macrodomain be controlled as a thermodynamic
pivot point — by allosteric stabilization of distinct conformational
states or by PROTAC-based physical degradation — to restore host
PARP9/DTX3L-dependent antiviral ADP-ribosylation and arrest viral
replication, and is this strategy broadly active across coronaviruses?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
- pathophysiology#Host PARP9/DTX3L Antiviral ADP-Ribosylation
rationale: >-
The Nsp3 Mac1 macrodomain is a conserved, structurally tractable viral
enzyme that selectively hydrolyzes the end product of the host IFN-PARP
antiviral program. Active-site inhibitors target the ADP-ribose pocket
directly, but the broader interactome framing suggests an alternative:
stabilize defined conformational states of Mac1 with allosteric binders to
test how each conformation reshapes the host PARP-mediated antiviral
response, or eliminate the protein outright with a viral-protein-directed
PROTAC warhead. Because Mac1 folds are conserved across SARS-CoV-2,
SARS-CoV, and MERS-CoV, conformational stabilizers or degraders may have
broad anti-coronavirus activity — the kind of pivot-point control that
distinguishes a thermodynamic interactome framing from single-enzyme
inhibition.
Both arms of the question are open at the level of chemical matter, not
merely of biology. No allosteric site has been identified or characterized
on any viral macrodomain; the only validated macrodomain allosteric ligand
series remains GeA-69 against human PARP14 macrodomain 2, whose
selectivity derives from PARP14-specific features. No Mac1-directed PROTAC
has been designed, synthesized, or tested, and every published SARS-CoV-2
degrader targets a standalone viral protein rather than a domain embedded
in the membrane-associated nsp3 polyprotein. The third CACHE challenge
screened 1739 candidate ligands from 23 groups and returned only canonical
adenine-mimetic orthosteric chemotypes, so community hit-finding has not
yet produced a non-orthosteric starting point either.
The comparator arm has meanwhile moved. Active-site inhibition now has in
vivo pharmacological proof of concept (AVI-4206) and an independent
chemotype that represses coronavirus replication, and serial passage under
that second chemotype has already produced a resistant Mac1 double mutant
that is itself attenuated in mice. Allosteric or degradation-based control
therefore has to demonstrate specific added value in breadth, resistance
profile, or efficacy, not merely that it works.
evidence:
- reference: PMID:40407321
reference_title: "Identification of a series of pyrrolo-pyrimidine-based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Recombinant virus with these mutations had enhanced replication compared
with the WT virus when treated with 5a, demonstrating the specificity of
these compounds during infection. However, this virus is highly
attenuated in vivo, indicating that drug resistance emerged at the
expense of viral fitness.
explanation: >-
Establishes the resistance baseline this gap must be measured against.
Escape from an active-site Mac1 inhibitor is achievable by serial
passage but costs viral fitness, so any claim that conformational or
degradation-based control offers a resistance advantage now has a
concrete comparator rather than an empty field.
- reference: PMID:41565251
reference_title: "CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Twenty-three groups deployed diverse design strategies to collectively
select 1739 ligand candidates. While over 85% of the designed molecules
were chemically novel, the best experimentally confirmed hits were
structurally similar to previously published compounds.
explanation: >-
A community-scale hit-finding effort against Mac1 recovered the known
orthosteric chemotype, which is why the absence of a non-orthosteric
chemical starting point is recorded here as a knowledge gap rather than
as a gap in effort.
proposed_experiments:
- experiment_id: exp_covid_mac1_allosteric_pivot
name: Allosteric Mac1 conformational stabilization versus PROTAC degradation in SARS-CoV-2-infected airway organoids
description: >-
Infect human airway organoids and ACE2/TMPRSS2-positive lung epithelial
lines with authentic SARS-CoV-2 and treat with (a) active-site Mac1
inhibitors, (b) allosteric Mac1 binders tuned to stabilize discrete
conformational states, and (c) a viral-Mac1-directed PROTAC warhead.
Read out viral genome replication, infectious virus production, host
PARP9/DTX3L-mediated ADP-ribosylation marks on host substrates, interferon-stimulated
gene induction, and downstream cytokine and tissue-damage
signatures. Repeat across SARS-CoV-2, SARS-CoV, and MERS-CoV Mac1
orthologs to test pan-coronavirus activity.
experiment_type:
preferred_term: controlled perturbation experiment
model_systems:
- name: Human airway organoid panel
description: >-
ACE2/TMPRSS2-positive bronchial and alveolar organoids derived from
human donors, used to capture native cellular tropism and innate
immune responses to SARS-CoV-2.
experimental_model_type: ORGANOID
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
tissue_term:
preferred_term: lung
term:
id: UBERON:0002048
label: lung
cell_types:
- preferred_term: ciliated cell
term:
id: CL:0000064
label: ciliated cell
- preferred_term: pulmonary alveolar type 2 cell
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
perturbations:
- name: Allosteric Mac1 conformational stabilization
target: pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
description: >-
Small-molecule binders that stabilize defined conformational states of
Mac1 to test conformation-specific impact on host ADP-ribosylation
and viral replication.
- name: Mac1 PROTAC degradation
target: pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
description: >-
Viral-protein-directed PROTAC warhead recruiting host E3 ubiquitin
ligase to physically degrade Nsp3 Mac1 in infected cells.
- name: Active-site Mac1 inhibition (comparator)
target: pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
description: >-
Direct ADP-ribose-pocket inhibitor used as comparator to distinguish
conformational and degradation modes of pivot control from canonical
active-site blockade.
readouts:
- name: Viral genome replication and infectious virus output
target: pathophysiology#Enhanced Viral Replication and Tissue Pathology
biological_processes:
- preferred_term: viral life cycle
term:
id: GO:0019058
label: viral life cycle
direction: NEGATIVE
- name: Host PARP9/DTX3L-dependent ADP-ribosylation rescue
target: pathophysiology#Host PARP9/DTX3L Antiviral ADP-Ribosylation
biological_processes:
- preferred_term: protein poly-ADP-ribosylation
term:
id: GO:0070212
label: protein poly-ADP-ribosylation
direction: POSITIVE
interpretation: >-
Restoration of host ADP-ribosylation marks alongside suppression of
viral replication would support Mac1 inactivation (allosteric or
PROTAC) as the causal link between interactome rebalancing and
antiviral control.
decision_criterion: >-
The macrodomain pivot model is supported if either allosteric
conformational stabilization or PROTAC degradation of Mac1 (a) restores
host PARP9/DTX3L-dependent ADP-ribosylation, (b) suppresses SARS-CoV-2
replication in human airway organoids, and (c) shows comparable activity
against SARS-CoV and MERS-CoV Mac1 orthologs, supporting a pan-CoV
mechanism.
would_support:
- pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
- pathophysiology#Host PARP9/DTX3L Antiviral ADP-Ribosylation
evidence:
- reference: PMID:33158944
reference_title: "The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus
(MERS-CoV) Mac1 domains exhibit similar structural folds, and all 3
proteins bound to ADP-ribose with affinities in the low micromolar
range
explanation: >-
Structural conservation of Mac1 across coronaviruses supports the
feasibility of a pan-CoV pivot-control strategy.
- reference: PMID:34358560
reference_title: "The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
ectopic expression of the SARS-CoV-2 Nsp3 macrodomain reverses this
modification in human cells
explanation: >-
The ectopic-Mac1 reversal phenotype is the operational readout that
Mac1 inactivation experiments must rescue.
- discussion_id: gap_covid_mac1_therapy_interferon_competence
prompt: >-
Mac1-directed therapy works by lifting viral suppression of host
ADP-ribosylation, so its benefit is predicted to depend on the patient's
own interferon competence. Does a Mac1 inhibitor retain efficacy in the
roughly one in five patients with critical COVID-19 who carry anti-type-I
interferon autoantibodies or an inborn error of type I interferon
immunity, and should interferon autoantibody status therefore be a
companion diagnostic rather than an exclusion?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Nsp3 Macrodomain De-ADP-Ribosylation Countermeasure
- pathophysiology#RNA Virus-Induced Interferon and PARP Activation
rationale: >-
Every published Mac1 inhibitor whose mechanism has been dissected acts
through immune restoration rather than through direct antiviral blockade,
and in both compound series the cellular antiviral effect is explicitly
interferon dependent. That makes host interferon competence a gate on the
entire therapeutic strategy, and the gate is not hypothetical: inborn
errors of type I interferon immunity account for 1 to 5 percent of
unvaccinated patients with critical pneumonia and anti-interferon
autoantibodies for another 15 to 20 percent, so the patients most likely
to need a novel antiviral are enriched for the defect that would blunt it.
The gap is that this has never been tested. No Mac1 inhibitor has entered
a clinical trial, so no cohort stratified by interferon autoantibody
status or by interferon-stimulated gene score exists, and the preclinical
interferon dependence has only been shown by adding or withholding
interferon gamma in culture, not by comparing hosts that differ in
endogenous type I interferon capacity. Resolving it needs either an animal
model with defined type I interferon pathway loss treated with an
active-site Mac1 inhibitor, or prospective collection of anti-interferon
autoantibody status in any future trial. The answer bears directly on the
Mac1 pivot hypothesis's claim of broad activity, because the limitation
applies equally to active-site, allosteric, and degradation-based
approaches.
evidence:
- reference: PMID:37196358
reference_title: "Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identifying inborn errors of type I interferon (IFN) immunity in 1-5% of
unvaccinated patients with critical pneumonia, and their autoimmune
phenocopy, autoantibodies against type I IFN, in another 15-20% of cases
explanation: >-
Quantifies the patient fraction in whom the host arm of the Mac1
therapeutic mechanism is already compromised, which is what makes the
efficacy question a real stratification problem rather than a
theoretical caveat.
- reference: PMID:41258893
reference_title: "The Mac1 ADP-ribosylhydrolase is a therapeutic target for SARS-CoV-2."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Standard cellular models indicate that AVI-4206 has high target
engagement and can weakly inhibit viral replication in a gamma
interferon- and Mac1 catalytic activity-dependent manner.
explanation: >-
Establishes the dependence itself: target engagement alone does not
produce antiviral activity, and the effect requires both interferon
signaling and Mac1 catalysis. This is the mechanistic reason to expect
reduced benefit in interferon-deficient patients.
- reference: PMID:40407321
reference_title: "Identification of a series of pyrrolo-pyrimidine-based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Furthermore, 5c and 6e inhibited SARS-CoV-2 replication only in the
presence of IFN
explanation: >-
An independent chemical series reproduces the same interferon
dependence, so the constraint is a property of Mac1 inhibition rather
than of one compound.
- discussion_id: gap_covid_pancreatic_beta_cell_tropism
prompt: >-
Does SARS-CoV-2 directly infect and damage pancreatic beta cells during
acute COVID-19, or is acute hyperglycemia driven predominantly by systemic
inflammation, HPA-axis stress, and metabolic dysregulation in peripheral
insulin-sensitive tissues?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#SARS-CoV-2 Spike-Mediated Entry via ACE2 and TMPRSS2
rationale: >-
Post-acute SARS-CoV-2 infection has been associated with new-onset diabetes,
raising the mechanistic question of direct viral pancreatic tropism vs.
systemic inflammation as the driver. A comprehensive post-pandemic review
(Said et al. 2026, Diabetologia) identifies conflicting evidence on whether
SARS-CoV-2 directly infects pancreatic beta cells during acute infection,
or whether acute hyperglycemia and persistent metabolic dysfunction post-COVID
result from HPA-axis stress, pro-inflammatory cytokines (TNF, IL-6, IL-1beta),
and reduced peripheral insulin sensitivity. This distinction is mechanistically
consequential: direct beta-cell tropism could produce permanent damage and
predict Type 1-like post-COVID diabetes, whereas inflammation-mediated
dysfunction would predict reversible Type 2 hyperglycemia. Resolution of this
branch informs the mechanistic link to post-COVID diabetes development modeled
in Long_COVID entry.
evidence:
- reference: PMID:42362970
reference_title: "SARS-CoV-2 and diabetes: a post-pandemic reappraisal."
supports: NO_EVIDENCE
evidence_source: OTHER
snippet: >-
We summarise proposed pathophysiological mechanisms, including the effects
of SARS-CoV-2 infection in the pancreas and on peripheral insulin-sensitive
tissues. We review key meta-analyses assessing the association between
COVID-19 and incident type 1 and type 2 diabetes and highlight strengths
and weaknesses of the epidemiologic studies
explanation: >-
Said et al. identify this mechanistic gap as a critical uncertainty,
noting conflicting evidence on direct pancreatic tropism vs. systemic
inflammation as drivers of acute hyperglycemia and post-COVID diabetes.
datasets:
- accession: ega:EGAS00001004450
title: Suppressive granulocytes are an indicator of severe disease in COVID-19
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("COVID-19"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004474
title: Peripheral immunoprofiling of stratifies COVID-19 patients based on disease-specific neutrophil signatures
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("COVID-19"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004481
title: Single-cell analysis of airway samples identifies immune cell activation correlating with COVID-19 disease severity
description: To investigate the immune response and mechanisms associated with severe COVID-19, we performed single-cell RNA-seq on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from 5 healthy controls. We identified airway epithelial cell types and states vulnerable to SARS-CoV-2 infection. In COVID-19 patients, epithelial cells showed an average threefold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
publication: PMID:32591762
notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("COVID-19"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST002477
title: Neutrophil metabolomics in COVID-19
notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("COVID-19"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST002087
title: Profiling metabolites and lipoproteins in COMETA, an Italian cohort of COVID-19 patients
notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("COVID-19"). Retrieved 2026-08-02.
- accession: massive:MSV000085703
title: Large-scale Multi-omic Analysis of COVID-19 Severity
description: We performed RNA-Seq and high-resolution mass spectrometry on 128 blood samples from COVID-19 positive and negative patients with diverse disease severities. Over 17,000 transcripts, proteins, metabolites, and lipids were quantified and associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation.
notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("COVID-19"). Retrieved 2026-08-02.
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