Plague

◆

Subtypes

3

Bubonic Plague

Most common form, resulting from flea bite inoculation. Y. pestis travels to regional lymph nodes, causing painful swollen lymph nodes (buboes), fever, and prostration. Without treatment, case fatality is approximately 40-60%.

Show evidence (1 reference)

PMID:32435802 SUPPORT

"Most patients had primary bubonic (63%), pneumonic (21%), or septicemic (5%) plague, with associated case fatality rates of 17%, 27%, and 38%, respectively."

Confirms bubonic plague as the most common clinical form at 63% of cases.

Septicemic Plague

Bloodstream infection without prominent bubo formation, or secondary to bubonic plague. Characterized by disseminated intravascular coagulation, purpura, and multi-organ failure. Highest case fatality among treated patients.

Show evidence (1 reference)

PMID:32435802 SUPPORT

"Most patients had primary bubonic (63%), pneumonic (21%), or septicemic (5%) plague, with associated case fatality rates of 17%, 27%, and 38%, respectively."

Septicemic plague accounts for approximately 5% of cases but carries the highest treated case fatality rate at 38%.

Pneumonic Plague

Infection of the lungs, either primary (from aerosol inhalation) or secondary (hematogenous spread from bubo). Transmissible person-to-person via respiratory droplets. Rapidly fatal without treatment within 48 hours.

Show evidence (1 reference)

PMID:30940874 SUPPORT

"the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague)"

Confirms the extreme lethality and rapid progression of pneumonic plague.

⚙

Pathophysiology

8

Flea-Mediated Transmission

Y. pestis is transmitted to humans through the bite of an infected flea. The bacterium colonizes the flea midgut and forms a biofilm that blocks the proventriculus, causing the flea to regurgitate bacteria into the bite wound during feeding attempts.

Skin UBERON:0002097

Downstream

Type III Secretion System Deployment After inoculation into the dermis, Y. pestis deploys its type III secretion system upon contact with host immune cells.

Show evidence (1 reference)

PMID:30940874 SUPPORT

"Plague is a vector-borne disease caused by Yersinia pestis. Transmitted by fleas from rodent reservoirs, Y. pestis emerged <6000 years ago from an enteric bacterial ancestor through events of gene gain and genome reduction."

Establishes flea-mediated vector transmission as the primary route of Y. pestis infection.

Type III Secretion System Deployment

Upon contact with host immune cells, Y. pestis deploys a type III secretion system (T3SS) encoded on the pYV/pCD1 virulence plasmid. The T3SS forms a needle-like injectisome that directly delivers Yop effector proteins into the cytoplasm of target immune cells.

Macrophage CL:0000235 Neutrophil CL:0000775 Dendritic Cell CL:0000451

Downstream

Yop Effector Injection and Immune Subversion The T3SS injects multiple Yop effector proteins that each target distinct immune cell signaling pathways.

Show evidence (2 references)

PMID:24198067 SUPPORT

"Within the host cell, the Yop effector proteins function to inhibit bacterial phagocytosis and to suppress the production of pro-inflammatory cytokines."

Describes the T3SS-delivered Yop effectors and their functions within host cells.

PMID:30940874 SUPPORT

"A complex set of virulence determinants, including the Yersinia outer-membrane proteins (Yops), the broad-range protease Pla, pathogen-associated molecular patterns (PAMPs), and iron capture systems play critical roles in the molecular strategies that Y. pestis employs to subvert the human immune system"

Confirms the multi-factorial virulence strategy including Yops and Pla protease.

Yop Effector Injection and Immune Subversion

Individual Yop effector proteins target distinct immune cell functions. YopH dephosphorylates focal adhesion proteins to block phagocytosis. YopE and YopT inactivate Rho GTPases controlling cytoskeleton dynamics. YopJ/YopP prevents NF-kappaB activation, suppressing pro-inflammatory cytokine production.

Phagocytosis GO:0006909 ↓ DECREASED Innate immune response GO:0045087 ↓ DECREASED

Downstream

Phagocytosis Inhibition and Bacterial Replication Combined Yop-mediated suppression of phagocytosis allows unrestricted extracellular bacterial replication.

Show evidence (1 reference)

PMID:10922034 SUPPORT In Vitro

"YopH is a powerful phosphotyrosine phosphatase playing an antiphagocytic role by dephosphorylating several focal adhesion proteins. YopE and YopT contribute to antiphagocytic effects by inactivating GTPases controlling cytoskeleton dynamics. YopP/YopJ plays an anti-inflammatory role by..."

Details the specific molecular mechanisms of each Yop effector in immune evasion.

Phagocytosis Inhibition and Bacterial Replication

The combined effect of Yop-mediated immune subversion is that macrophages and neutrophils cannot effectively engulf and kill Y. pestis. This allows unrestricted extracellular bacterial replication at the inoculation site, enabling dissemination to draining lymph nodes.

Defense response to Gram-negative bacterium GO:0050829 ↓ DECREASED

Downstream

Lymph Node Colonization and Bubo Formation Bacteria disseminate from the inoculation site via lymphatics to regional lymph nodes, where they replicate massively.

Lymph Node Colonization and Bubo Formation

After immune evasion at the inoculation site, Y. pestis disseminates to draining lymph nodes where it replicates massively, causing the characteristic painful swollen lymph nodes (buboes) that define bubonic plague.

Macrophage CL:0000235 Neutrophil CL:0000775

Inflammatory response GO:0006954

Lymph node UBERON:0000029

Downstream

Systemic Spread and Septicemic Plague Bacteria can escape from lymph nodes into the bloodstream, causing septicemia, disseminated intravascular coagulation, and multi-organ failure.

Show evidence (2 references)

PMID:30940874 SUPPORT

"allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague)"

Confirms that lymph nodes are a primary site of Y. pestis replication in bubonic plague.

PMID:12951845 SUPPORT

"Yersinia pestis is the cause of plague, an illness that may manifest in bubonic, pneumonic, or septicemic form. Plague has killed an estimated 200 million humans throughout history"

Establishes that bubonic form involves lymph node involvement and that plague has been historically devastating.

Systemic Spread and Septicemic Plague

When Y. pestis enters the bloodstream from infected lymph nodes or directly, it causes septicemia with disseminated intravascular coagulation, purpura (historically giving the disease its 'Black Death' name), and multi-organ failure.

Monocyte CL:0000576

Inflammatory response GO:0006954 ↑ INCREASED Apoptotic process GO:0006915 ↑ INCREASED

Downstream

Pneumonic Plague Hematogenous spread to the lungs can cause secondary pneumonic plague.

Show evidence (2 references)

PMID:10922034 SUPPORT In Vitro

"YopP/YopJ plays an anti-inflammatory role by preventing the activation of the transcription factor NF-kappaB. It also induces rapid apoptosis of macrophages."

Yop-mediated macrophage apoptosis contributes to uncontrolled bacterial dissemination and systemic disease.

PMID:15207311 SUPPORT

"Bubonic disease, pneumonic plague, and septicemic plague are seen in addition to a number of other less common manifestations."

Confirms the clinical spectrum including septicemic plague.

Pneumonic Plague

Lung infection with Y. pestis, arising either from hematogenous spread (secondary) or direct inhalation of infectious respiratory droplets (primary). Pneumonic plague is characterized by fulminant pneumonia, hemoptysis, and respiratory failure. It is the only form transmissible person-to-person and is nearly 100% fatal without early antibiotic treatment.

Macrophage CL:0000235 Neutrophil CL:0000775

Innate immune response GO:0045087 ↓ DECREASED Inflammatory response GO:0006954 ↑ INCREASED

Lung UBERON:0002048

Show evidence (2 references)

PMID:30940874 SUPPORT

"the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague)"

Confirms the extreme lethality and rapidity of pneumonic plague without treatment.

PMID:24198067 SUPPORT

"Yersinia pestis, the etiologic agent of plague, utilizes a type III secretion system (T3SS) to subvert the defenses of its mammalian hosts."

T3SS-mediated immune evasion applies to pulmonary infection as well.

ERAP2 Evolutionary Selection

The Black Death pandemic of 1346-1353 exerted powerful selective pressure on the human genome, particularly at immune loci. The rs2549794 variant in ERAP2 was strongly selected, as the allele producing a full-length ERAP2 transcript conferred improved ability to control intracellular Y. pestis in macrophages. This same protective allele is now associated with increased susceptibility to autoimmune diseases, representing a classic case of antagonistic pleiotropy shaped by past pandemic selection.

Immune response GO:0006955 Proteolysis GO:0006508

Show evidence (2 references)

PMID:36261521 SUPPORT In Vitro

"The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages."

Directly demonstrates that ERAP2 rs2549794 was selected during the Black Death and confers functional immune advantage against Y. pestis.

PMID:36261521 SUPPORT Human Clinical

"we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease."

Demonstrates antagonistic pleiotropy where plague-protective alleles now increase autoimmune disease risk.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

10

Blood 2

Purpura HP:0000979

Disseminated Intravascular Coagulation HP:0005521

Cardiovascular 2

Bubo (Lymphadenopathy) HP:0002716

Painful swollen lymph nodes (buboes) are the defining feature of bubonic plague; cited abstracts mention "bubonic disease" by name but do not describe the lymphadenopathy in their text.

Splenomegaly HP:0001744

Immune 2

Pneumonia HP:0002090

Show evidence (1 reference)

PMID:30940874 SUPPORT

"allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague)"

Confirms lung involvement as a primary site in pneumonic plague.

Sepsis HP:0100806

Metabolism 1

Fever HP:0001945

Fever is a cardinal presenting feature of all forms of plague; cited abstracts do not explicitly name it in their text.

Respiratory 2

Dyspnea HP:0002094

Cough HP:0012735

Constitutional 1

Chest Pain HP:0100749

🧬

Genetic Associations

1

ERAP2 (Evolutionary selection during Black Death)

Gene: ERAP2 hgnc:29499

Show evidence (1 reference)

PMID:36261521 SUPPORT In Vitro

"The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages."

ERAP2 rs2549794 was under positive selection during the Black Death and provides functional immune advantage.

💊

Medical Actions

3

Aminoglycoside Antibiotics

Action: aminoglycoside antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Streptomycin and gentamicin are first-line treatments for plague. Aminoglycosides have the longest track record of efficacy against Y. pestis infection.

Show evidence (2 references)

PMID:32435802 SUPPORT

"Treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in illness but can have serious side effects."

Confirms aminoglycosides as effective first-line treatment for plague.

PMID:32435800 SUPPORT

"Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague."

Aggregate data confirms aminoglycosides among the most effective treatments for plague.

Tetracycline Antibiotics

Action: tetracycline antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Doxycycline and other tetracyclines are effective alternatives for plague treatment and prophylaxis. Used when aminoglycosides are contraindicated.

Show evidence (1 reference)

PMID:32435800 SUPPORT

"Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague."

Confirms tetracyclines among the most effective plague treatments.

Supportive Care

Action: Supportive Care NCIT:C15747

Intensive supportive care including fluid resuscitation, vasopressor support, and management of DIC complications for severe septicemic and pneumonic plague.

📈

Progression

3

Onset

Incubation: 1-7 days

Incubation period is typically 1-7 days for bubonic plague (usually 2-6 days) and 1-3 days for pneumonic plague. Onset is acute with sudden fever, chills, and malaise.

Acute

Rapid progression to bubo formation (bubonic), septicemia, or pneumonia depending on clinical form. Without treatment, pneumonic plague is fatal within 48 hours and bubonic plague within a week.

Show evidence (1 reference)

PMID:30940874 SUPPORT

"the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague)"

Confirms the timeline of untreated plague progression.

Resolution or Death

With prompt antibiotic treatment, most patients recover. Without treatment, case fatality approaches 100% for pneumonic and septicemic forms. Even with treatment, overall case fatality is approximately 20%.

Show evidence (1 reference)

PMID:32435802 SUPPORT

"The case fatality rate was 20% overall."

Confirms 20% overall case fatality even with treatment.

📊

Prevalence

1

Global

Annual Incidence <1 in 1,000,000 per year

Approximately 2,000 cases reported annually to the WHO worldwide (a global annual case count, not a point prevalence; ~0.25 cases per million people). Endemic foci in Africa, Asia, and the Americas concentrate the burden well above the global rate. Madagascar, Democratic Republic of Congo, and Peru report the majority of modern cases.

Show evidence (1 reference)

PMID:12951845 SUPPORT

"Approximately 2,000 cases of plague are reported each year to the World Health Organization, and concern has been raised about the possible use of Y pestis as an agent of bioterrorism."

Confirms approximately 2,000 annual cases reported globally.

🦠

Infectious Agent

1

Yersinia pestis

Yersinia pestis NCBITaxon:632

Show evidence (1 reference)

PMID:12951845 SUPPORT

"Yersinia pestis is the cause of plague, an illness that may manifest in bubonic, pneumonic, or septicemic form."

Establishes Y. pestis as the causative agent of all forms of plague.

↔️

Transmission

3

Flea-borne Transmission

Primary route of plague transmission. Infected fleas (primarily Xenopsylla cheopis, the Oriental rat flea) transmit Y. pestis to humans during blood meals. The bacterium forms a biofilm in the flea's proventriculus, which is regurgitated during feeding.

Show evidence (1 reference)

PMID:30940874 SUPPORT

"Plague is a vector-borne disease caused by Yersinia pestis. Transmitted by fleas from rodent reservoirs"

Confirms the flea-borne vector transmission route from rodent reservoirs.

Respiratory Droplet Transmission

Person-to-person transmission occurs via respiratory droplets from patients with pneumonic plague. This is the only form of plague that can spread directly between humans.

Person-to-person respiratory droplet transmission is a defining feature of pneumonic plague; this is textbook knowledge not directly quoted in the abstract cache of cited references.

Direct Contact

Handling infected animals or tissues, particularly during skinning or butchering of infected rodents or other mammals.

{ }

Source YAML

click to show

name: Plague
creation_date: '2026-04-03T00:00:00Z'
category: Infectious Disease
description: >
Plague is a severe zoonotic disease caused by the Gram-negative bacterium
Yersinia pestis. Transmitted primarily by flea bites from infected rodent
reservoirs, Y. pestis can manifest as bubonic, septicemic, or pneumonic
plague. The bacterium deploys a type III secretion system to inject Yop
effector proteins into host immune cells, suppressing phagocytosis and
inflammatory responses. Without prompt antibiotic treatment, plague is
frequently fatal, particularly in its pneumonic and septicemic forms.
Historically, the Black Death pandemic of 1346-1353 killed an estimated
30-50% of the European population and exerted one of the strongest known
selective pressures on the human genome, notably driving selection of
immune-related variants such as the ERAP2 rs2549794 allele.
parents:
- Bacterial Infection
disease_term:
preferred_term: plague
term:
id: MONDO:0019095
label: plague
synonyms:
- Black Death
- Pestilence
- Bubonic Plague
- Pneumonic Plague
- Yersinia pestis infection
infectious_agent:
- name: Yersinia pestis
infectious_agent_term:
preferred_term: Yersinia pestis
term:
id: NCBITaxon:632
label: Yersinia pestis
evidence:
- reference: PMID:12951845
reference_title: "Yersinia pestis and the plague."
supports: SUPPORT
snippet: Yersinia pestis is the cause of plague, an illness that may manifest
in bubonic, pneumonic, or septicemic form.
explanation: Establishes Y. pestis as the causative agent of all forms of plague.
has_subtypes:
- name: Bubonic
display_name: Bubonic Plague
description: >
Most common form, resulting from flea bite inoculation. Y. pestis travels
to regional lymph nodes, causing painful swollen lymph nodes (buboes),
fever, and prostration. Without treatment, case fatality is approximately
40-60%.
evidence:
- reference: PMID:32435802
reference_title: "Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937-2019."
supports: SUPPORT
snippet: Most patients had primary bubonic (63%), pneumonic (21%), or
septicemic (5%) plague, with associated case fatality rates of 17%, 27%,
and 38%, respectively.
explanation: Confirms bubonic plague as the most common clinical form at 63%
of cases.
- name: Septicemic
display_name: Septicemic Plague
description: >
Bloodstream infection without prominent bubo formation, or secondary to
bubonic plague. Characterized by disseminated intravascular coagulation,
purpura, and multi-organ failure. Highest case fatality among treated
patients.
evidence:
- reference: PMID:32435802
reference_title: "Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937-2019."
supports: SUPPORT
snippet: Most patients had primary bubonic (63%), pneumonic (21%), or
septicemic (5%) plague, with associated case fatality rates of 17%, 27%,
and 38%, respectively.
explanation: Septicemic plague accounts for approximately 5% of cases but
carries the highest treated case fatality rate at 38%.
- name: Pneumonic
display_name: Pneumonic Plague
description: >
Infection of the lungs, either primary (from aerosol inhalation) or
secondary (hematogenous spread from bubo). Transmissible person-to-person
via respiratory droplets. Rapidly fatal without treatment within 48 hours.
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: the rapid onset of death in the absence of antibiotic treatment
(less than a week for bubonic plague and <48 h for pneumonic plague)
explanation: Confirms the extreme lethality and rapid progression of
pneumonic plague.
pathophysiology:
- name: Flea-Mediated Transmission
description: >
Y. pestis is transmitted to humans through the bite of an infected flea.
The bacterium colonizes the flea midgut and forms a biofilm that blocks
the proventriculus, causing the flea to regurgitate bacteria into the
bite wound during feeding attempts.
locations:
- preferred_term: Skin
term:
id: UBERON:0002097
label: skin of body
downstream:
- target: Type III Secretion System Deployment
description: >
After inoculation into the dermis, Y. pestis deploys its type III
secretion system upon contact with host immune cells.
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: Plague is a vector-borne disease caused by Yersinia pestis.
Transmitted by fleas from rodent reservoirs, Y. pestis emerged <6000
years ago from an enteric bacterial ancestor through events of gene gain
and genome reduction.
explanation: Establishes flea-mediated vector transmission as the primary
route of Y. pestis infection.
- name: Type III Secretion System Deployment
description: >
Upon contact with host immune cells, Y. pestis deploys a type III
secretion system (T3SS) encoded on the pYV/pCD1 virulence plasmid. The
T3SS forms a needle-like injectisome that directly delivers Yop effector
proteins into the cytoplasm of target immune cells.
cell_types:
- preferred_term: Macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: Neutrophil
term:
id: CL:0000775
label: neutrophil
- preferred_term: Dendritic Cell
term:
id: CL:0000451
label: dendritic cell
downstream:
- target: Yop Effector Injection and Immune Subversion
description: >
The T3SS injects multiple Yop effector proteins that each target
distinct immune cell signaling pathways.
evidence:
- reference: PMID:24198067
reference_title: "The Yersinia pestis type III secretion system: expression, assembly and role in the evasion of host defenses."
supports: SUPPORT
snippet: Within the host cell, the Yop effector proteins function to
inhibit bacterial phagocytosis and to suppress the production of
pro-inflammatory cytokines.
explanation: Describes the T3SS-delivered Yop effectors and their
functions within host cells.
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: A complex set of virulence determinants, including the Yersinia
outer-membrane proteins (Yops), the broad-range protease Pla,
pathogen-associated molecular patterns (PAMPs), and iron capture systems
play critical roles in the molecular strategies that Y. pestis employs to
subvert the human immune system
explanation: Confirms the multi-factorial virulence strategy including
Yops and Pla protease.
- name: Yop Effector Injection and Immune Subversion
description: >
Individual Yop effector proteins target distinct immune cell functions.
YopH dephosphorylates focal adhesion proteins to block phagocytosis.
YopE and YopT inactivate Rho GTPases controlling cytoskeleton dynamics.
YopJ/YopP prevents NF-kappaB activation, suppressing pro-inflammatory
cytokine production.
biological_processes:
- preferred_term: Phagocytosis
term:
id: GO:0006909
label: phagocytosis
modifier: DECREASED
- preferred_term: Innate immune response
term:
id: GO:0045087
label: innate immune response
modifier: DECREASED
downstream:
- target: Phagocytosis Inhibition and Bacterial Replication
description: >
Combined Yop-mediated suppression of phagocytosis allows unrestricted
extracellular bacterial replication.
evidence:
- reference: PMID:10922034
reference_title: "Molecular and cell biology aspects of plague."
supports: SUPPORT
snippet: YopH is a powerful phosphotyrosine phosphatase playing an
antiphagocytic role by dephosphorylating several focal adhesion proteins.
YopE and YopT contribute to antiphagocytic effects by inactivating
GTPases controlling cytoskeleton dynamics. YopP/YopJ plays an
anti-inflammatory role by preventing the activation of the transcription
factor NF-kappaB.
explanation: Details the specific molecular mechanisms of each Yop effector
in immune evasion.
evidence_source: IN_VITRO
- name: Phagocytosis Inhibition and Bacterial Replication
description: >
The combined effect of Yop-mediated immune subversion is that
macrophages and neutrophils cannot effectively engulf and kill Y. pestis.
This allows unrestricted extracellular bacterial replication at the
inoculation site, enabling dissemination to draining lymph nodes.
biological_processes:
- preferred_term: Defense response to Gram-negative bacterium
term:
id: GO:0050829
label: defense response to Gram-negative bacterium
modifier: DECREASED
downstream:
- target: Lymph Node Colonization and Bubo Formation
description: >
Bacteria disseminate from the inoculation site via lymphatics to
regional lymph nodes, where they replicate massively.
- name: Lymph Node Colonization and Bubo Formation
description: >
After immune evasion at the inoculation site, Y. pestis disseminates to
draining lymph nodes where it replicates massively, causing the
characteristic painful swollen lymph nodes (buboes) that define bubonic
plague.
cell_types:
- preferred_term: Macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: Neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: Lymph node
term:
id: UBERON:0000029
label: lymph node
downstream:
- target: Systemic Spread and Septicemic Plague
description: >
Bacteria can escape from lymph nodes into the bloodstream, causing
septicemia, disseminated intravascular coagulation, and multi-organ
failure.
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: allowing unrestricted bacterial replication in lymph nodes
(bubonic plague) and in lungs (pneumonic plague)
explanation: Confirms that lymph nodes are a primary site of Y. pestis
replication in bubonic plague.
- reference: PMID:12951845
reference_title: "Yersinia pestis and the plague."
supports: SUPPORT
snippet: Yersinia pestis is the cause of plague, an illness that may
manifest in bubonic, pneumonic, or septicemic form. Plague has killed an
estimated 200 million humans throughout history
explanation: Establishes that bubonic form involves lymph node involvement
and that plague has been historically devastating.
- name: Systemic Spread and Septicemic Plague
description: >
When Y. pestis enters the bloodstream from infected lymph nodes or
directly, it causes septicemia with disseminated intravascular
coagulation, purpura (historically giving the disease its 'Black Death'
name), and multi-organ failure.
cell_types:
- preferred_term: Monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: INCREASED
- preferred_term: Apoptotic process
term:
id: GO:0006915
label: apoptotic process
modifier: INCREASED
downstream:
- target: Pneumonic Plague
description: >
Hematogenous spread to the lungs can cause secondary pneumonic plague.
evidence:
- reference: PMID:10922034
reference_title: "Molecular and cell biology aspects of plague."
supports: SUPPORT
snippet: "YopP/YopJ plays an anti-inflammatory role by preventing the
activation of the transcription factor NF-kappaB. It also induces rapid
apoptosis of macrophages."
explanation: Yop-mediated macrophage apoptosis contributes to uncontrolled
bacterial dissemination and systemic disease.
evidence_source: IN_VITRO
- reference: PMID:15207311
reference_title: "Plague."
supports: SUPPORT
snippet: Bubonic disease, pneumonic plague, and septicemic plague are seen
in addition to a number of other less common manifestations.
explanation: Confirms the clinical spectrum including septicemic plague.
- name: Pneumonic Plague
description: >
Lung infection with Y. pestis, arising either from hematogenous spread
(secondary) or direct inhalation of infectious respiratory droplets
(primary). Pneumonic plague is characterized by fulminant pneumonia,
hemoptysis, and respiratory failure. It is the only form transmissible
person-to-person and is nearly 100% fatal without early antibiotic
treatment.
cell_types:
- preferred_term: Macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: Neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: Innate immune response
term:
id: GO:0045087
label: innate immune response
modifier: DECREASED
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: INCREASED
locations:
- preferred_term: Lung
term:
id: UBERON:0002048
label: lung
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: the rapid onset of death in the absence of antibiotic treatment
(less than a week for bubonic plague and <48 h for pneumonic plague)
explanation: Confirms the extreme lethality and rapidity of pneumonic
plague without treatment.
- reference: PMID:24198067
reference_title: "The Yersinia pestis type III secretion system: expression, assembly and role in the evasion of host defenses."
supports: SUPPORT
snippet: Yersinia pestis, the etiologic agent of plague, utilizes a type
III secretion system (T3SS) to subvert the defenses of its mammalian
hosts.
explanation: T3SS-mediated immune evasion applies to pulmonary infection
as well.
- name: ERAP2 Evolutionary Selection
description: >
The Black Death pandemic of 1346-1353 exerted powerful selective pressure
on the human genome, particularly at immune loci. The rs2549794 variant
in ERAP2 was strongly selected, as the allele producing a full-length
ERAP2 transcript conferred improved ability to control intracellular
Y. pestis in macrophages. This same protective allele is now associated
with increased susceptibility to autoimmune diseases, representing a
classic case of antagonistic pleiotropy shaped by past pandemic selection.
biological_processes:
- preferred_term: Immune response
term:
id: GO:0006955
label: immune response
- preferred_term: Proteolysis
term:
id: GO:0006508
label: proteolysis
notes: >
ERAP2 encodes an endoplasmic reticulum aminopeptidase involved in
antigen processing for MHC class I presentation. The selected haplotype B
produces a full-length functional protein, while the alternative produces
a truncated, non-functional transcript.
evidence:
- reference: PMID:36261521
reference_title: "Evolution of immune genes is associated with the Black Death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The selected allele for one of these variants, rs2549794, is
associated with the production of a full-length (versus truncated)
ERAP2 transcript, variation in cytokine response to Y. pestis and
increased ability to control intracellular Y. pestis in macrophages.
explanation: Directly demonstrates that ERAP2 rs2549794 was selected
during the Black Death and confers functional immune advantage against
Y. pestis.
- reference: PMID:36261521
reference_title: "Evolution of immune genes is associated with the Black Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: we show that protective variants overlap with alleles that are
today associated with increased susceptibility to autoimmune diseases,
providing empirical evidence for the role played by past pandemics in
shaping present-day susceptibility to disease.
explanation: Demonstrates antagonistic pleiotropy where plague-protective
alleles now increase autoimmune disease risk.
phenotypes:
- name: Bubo (Lymphadenopathy)
category: Signs and Symptoms
description: >
Painful, swollen lymph nodes (buboes) in the inguinal, axillary, or
cervical region, characteristic of bubonic plague.
subtype: Bubonic
notes: >
Painful swollen lymph nodes (buboes) are the defining feature of bubonic
plague; cited abstracts mention "bubonic disease" by name but do not
describe the lymphadenopathy in their text.
phenotype_term:
preferred_term: Bubo (swollen lymph node)
term:
id: HP:0002716
label: Lymphadenopathy
- name: Fever
category: Signs and Symptoms
description: High fever, often with rigors, accompanying all forms of plague.
notes: >
Fever is a cardinal presenting feature of all forms of plague; cited
abstracts do not explicitly name it in their text.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
- name: Purpura
category: Signs and Symptoms
description: >
Skin hemorrhages (purpura and ecchymoses) resulting from disseminated
intravascular coagulation in septicemic plague, historically responsible
for the name 'Black Death'.
subtype: Septicemic
phenotype_term:
preferred_term: Purpura
term:
id: HP:0000979
label: Purpura
- name: Disseminated Intravascular Coagulation
category: Signs and Symptoms
description: >
Consumption coagulopathy with simultaneous thrombosis and hemorrhage,
a hallmark of septicemic plague leading to multi-organ failure.
subtype: Septicemic
phenotype_term:
preferred_term: Disseminated intravascular coagulation
term:
id: HP:0005521
label: Disseminated intravascular coagulation
- name: Pneumonia
category: Signs and Symptoms
description: >
Fulminant pneumonia with bloody sputum (hemoptysis), dyspnea, and
rapid respiratory failure in pneumonic plague.
subtype: Pneumonic
phenotype_term:
preferred_term: Pneumonia
term:
id: HP:0002090
label: Pneumonia
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: allowing unrestricted bacterial replication in lymph nodes
(bubonic plague) and in lungs (pneumonic plague)
explanation: Confirms lung involvement as a primary site in pneumonic plague.
- name: Dyspnea
category: Signs and Symptoms
description: Shortness of breath, especially in pneumonic plague.
subtype: Pneumonic
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
- name: Cough
category: Signs and Symptoms
description: Cough, often productive with bloody sputum, in pneumonic plague.
subtype: Pneumonic
phenotype_term:
preferred_term: Cough
term:
id: HP:0012735
label: Cough
- name: Sepsis
category: Signs and Symptoms
description: Systemic bacterial infection with organ dysfunction.
subtype: Septicemic
phenotype_term:
preferred_term: Sepsis
term:
id: HP:0100806
label: Sepsis
- name: Splenomegaly
category: Signs and Symptoms
description: Enlargement of spleen from systemic infection.
phenotype_term:
preferred_term: Splenomegaly
term:
id: HP:0001744
label: Splenomegaly
- name: Chest Pain
category: Signs and Symptoms
description: Pleuritic chest pain accompanying pneumonic plague.
subtype: Pneumonic
phenotype_term:
preferred_term: Chest pain
term:
id: HP:0100749
label: Chest pain
genetic:
- name: ERAP2
association: Evolutionary selection during Black Death
gene_term:
preferred_term: ERAP2
term:
id: hgnc:29499
label: ERAP2
notes: >
The rs2549794 variant near ERAP2 was strongly selected during the
1346-1353 Black Death pandemic. The selected allele produces a
full-length ERAP2 aminopeptidase that enhances control of intracellular
Y. pestis in macrophages through improved antigen processing. This
protective allele is now associated with increased susceptibility to
autoimmune diseases (antagonistic pleiotropy).
evidence:
- reference: PMID:36261521
reference_title: "Evolution of immune genes is associated with the Black Death."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The selected allele for one of these variants, rs2549794, is
associated with the production of a full-length (versus truncated)
ERAP2 transcript, variation in cytokine response to Y. pestis and
increased ability to control intracellular Y. pestis in macrophages.
explanation: ERAP2 rs2549794 was under positive selection during the
Black Death and provides functional immune advantage.
treatments:
- name: Aminoglycoside Antibiotics
description: >
Streptomycin and gentamicin are first-line treatments for plague.
Aminoglycosides have the longest track record of efficacy against
Y. pestis infection.
treatment_term:
preferred_term: aminoglycoside antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
evidence:
- reference: PMID:32435802
reference_title: "Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937-2019."
supports: SUPPORT
snippet: Treatment with aminoglycosides such as streptomycin or gentamicin
is effective when initiated early in illness but can have serious side
effects.
explanation: Confirms aminoglycosides as effective first-line treatment
for plague.
- reference: PMID:32435800
reference_title: "Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939-2019."
supports: SUPPORT
snippet: Tetracyclines, chloramphenicol, and aminoglycosides were
associated with the lowest case fatality rates of all antimicrobials
used for treatment of plague.
explanation: Aggregate data confirms aminoglycosides among the most
effective treatments for plague.
- name: Tetracycline Antibiotics
description: >
Doxycycline and other tetracyclines are effective alternatives for
plague treatment and prophylaxis. Used when aminoglycosides are
contraindicated.
treatment_term:
preferred_term: tetracycline antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
evidence:
- reference: PMID:32435800
reference_title: "Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939-2019."
supports: SUPPORT
snippet: Tetracyclines, chloramphenicol, and aminoglycosides were
associated with the lowest case fatality rates of all antimicrobials
used for treatment of plague.
explanation: Confirms tetracyclines among the most effective plague
treatments.
- name: Supportive Care
description: >
Intensive supportive care including fluid resuscitation, vasopressor
support, and management of DIC complications for severe septicemic
and pneumonic plague.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
transmission:
- name: Flea-borne Transmission
description: >
Primary route of plague transmission. Infected fleas (primarily Xenopsylla
cheopis, the Oriental rat flea) transmit Y. pestis to humans during blood
meals. The bacterium forms a biofilm in the flea's proventriculus, which
is regurgitated during feeding.
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: Plague is a vector-borne disease caused by Yersinia pestis.
Transmitted by fleas from rodent reservoirs
explanation: Confirms the flea-borne vector transmission route from
rodent reservoirs.
- name: Respiratory Droplet Transmission
description: >
Person-to-person transmission occurs via respiratory droplets from
patients with pneumonic plague. This is the only form of plague that
can spread directly between humans.
notes: >
Person-to-person respiratory droplet transmission is a defining feature
of pneumonic plague; this is textbook knowledge not directly quoted in
the abstract cache of cited references.
- name: Direct Contact
description: >
Handling infected animals or tissues, particularly during skinning or
butchering of infected rodents or other mammals.
prevalence:
- population: Global
measure_type: ANNUAL_INCIDENCE
prevalence_class: BELOW_1_IN_1000000
notes: >
Approximately 2,000 cases reported annually to the WHO worldwide (a global
annual case count, not a point prevalence; ~0.25 cases per million people).
Endemic foci in Africa, Asia, and the Americas concentrate the burden well
above the global rate. Madagascar, Democratic Republic of Congo, and Peru
report the majority of modern cases.
evidence:
- reference: PMID:12951845
reference_title: "Yersinia pestis and the plague."
supports: SUPPORT
snippet: Approximately 2,000 cases of plague are reported each year to
the World Health Organization, and concern has been raised about the
possible use of Y pestis as an agent of bioterrorism.
explanation: Confirms approximately 2,000 annual cases reported globally.
progression:
- phase: Onset
incubation_days: 1-7
notes: >
Incubation period is typically 1-7 days for bubonic plague (usually 2-6
days) and 1-3 days for pneumonic plague. Onset is acute with sudden
fever, chills, and malaise.
- phase: Acute
notes: >
Rapid progression to bubo formation (bubonic), septicemia, or
pneumonia depending on clinical form. Without treatment, pneumonic
plague is fatal within 48 hours and bubonic plague within a week.
evidence:
- reference: PMID:30940874
reference_title: "Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics."
supports: SUPPORT
snippet: the rapid onset of death in the absence of antibiotic treatment
(less than a week for bubonic plague and <48 h for pneumonic plague)
explanation: Confirms the timeline of untreated plague progression.
- phase: Resolution or Death
notes: >
With prompt antibiotic treatment, most patients recover. Without
treatment, case fatality approaches 100% for pneumonic and septicemic
forms. Even with treatment, overall case fatality is approximately 20%.
evidence:
- reference: PMID:32435802
reference_title: "Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937-2019."
supports: SUPPORT
snippet: The case fatality rate was 20% overall.
explanation: Confirms 20% overall case fatality even with treatment.
notes: >
The Black Death pandemic (1346-1353) is the single greatest mortality event
in recorded history, killing 30-50% of the European population. Ancient DNA
studies have confirmed Y. pestis as the causative agent and revealed that
plague lineages were already circulating in Neolithic Europe thousands of
years before the Black Death. Y. pestis evolved from the enteric pathogen
Yersinia pseudotuberculosis less than 6,000 years ago through gene gain and
genome reduction events.

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