🏷

Classifications

Harrison's Part

⚙

Pathophysiology

11

Ixodes-Borne Anaplasma Inoculation

Infected Ixodes ticks inoculate A. phagocytophilum and initiate the granulocytic intracellular infection that defines HGA.

symbiont entry into host GO:0044409

Downstream

PSGL-1-Mediated Neutrophil Entry Tick inoculation delivers organisms that then bind granulocyte receptors and enter neutrophils.

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne bacterial infection caused by Anaplasma phagocytophilum."

Establishes tick-borne A. phagocytophilum infection as the initiating exposure for HGA.

PSGL-1-Mediated Neutrophil Entry

A. phagocytophilum engages granulocyte receptors including PSGL-1 and its sialyl Lewis x cap to enter neutrophils and deliver effector cargo.

neutrophil CL:0000775

symbiont entry into host cell GO:0046718

Downstream

Anaplasma-Occupied Granulocyte Inclusion Receptor-dependent entry seeds the intracellular inclusion in which the bacterium can survive.

Show evidence (1 reference)

PMID:18485118 SUPPORT In Vitro

"P-selectin glycoprotein ligand-1 (PSGL-1) and the tetrasaccharide sialyl Lewis x (sLe(x)), which caps the PSGL-1 N-terminus, are confirmed A. phagocytophilum receptors."

Identifies PSGL-1 and sialyl Lewis x as host receptors used by A. phagocytophilum during granulocytic infection.

Anaplasma-Occupied Granulocyte Inclusion

The bacterium multiplies in granulocytes inside a protected inclusion, a niche that separates the organism from extracellular immune effectors and underlies the need for cell-penetrant therapy.

neutrophil CL:0000775

biological process involved in interaction with host GO:0051701

Downstream

AnkA-Driven NADPH Oxidase Silencing Intracellular organisms use a type IV secretion system to deliver AnkA into the host nucleus.

Ats-1 Anti-Apoptosis and Autophagy Hijacking Intracellular organisms deliver Ats-1 to mitochondria and autophagy initiation machinery.

Anaplasma Ribosomal Translation (Doxycycline Target) Intracellular Anaplasma remains dependent on its bacterial ribosome for protein synthesis.

Msp2(p44) Antigenic Variation Persistent intracellular organisms shuffle msp2(p44) pseudogenes to vary their major surface antigen.

Show evidence (1 reference)

PMID:17275372 SUPPORT REVIEW SYNTHESIS Other

"Anaplasma phagocytophilum, the causative agent of tick-borne fever (TBF) in sheep and cattle and human granulocytic anaplasmosis, has the unique ability to infect and multiply within neutrophils, eosinophils and monocytes, cells at the frontline of the immune system."

Review synthesis establishing multiplication of A. phagocytophilum in granulocytic host cells.

AnkA-Driven NADPH Oxidase Silencing

The type IV secretion effector AnkA traffics into the granulocyte nucleus, binds AT-rich DNA at antimicrobial defense genes, recruits HDAC1 at the CYBB promoter, and represses NADPH oxidase expression, reducing respiratory-burst killing.

negative regulation of respiratory burst GO:0060268 ↑ INCREASED

Downstream

Granulocytic Anaplasma Immune Evasion Silencing CYBB suppresses the NADPH-oxidase component of neutrophil oxidative killing and helps intracellular organisms avoid bactericidal attack.

Show evidence (2 references)

PMID:25996657 SUPPORT In Vitro

"Ankyrin A (AnkA), an A. phagocytophilum type IV secretion system effector, enters the granulocyte nucleus, binds stretches of AT-rich DNA and alters transcription of antimicrobial defence genes, including down-regulation of CYBB."

Establishes the nuclear AnkA effector and its repression of the CYBB NADPH-oxidase gene in granulocytes.

PMID:25996657 SUPPORT In Vitro

"Furthermore, a direct interaction between AnkA and HDAC1 was detected at the CYBB promoter, and was critical for AnkA-mediated CYBB repression."

Links AnkA recruitment of HDAC1 at the CYBB promoter to the silencing of the neutrophil oxidative-burst gene.

Ats-1 Anti-Apoptosis and Autophagy Hijacking

The A. phagocytophilum Ats-1 effector enters host mitochondria to suppress intrinsic apoptosis and also binds Beclin 1/Atg14L to nucleate autophagosomes that support the Anaplasma inclusion.

negative regulation of apoptotic process GO:0043066 ↑ INCREASED autophagosome assembly GO:0000045 ↑ INCREASED

Downstream

Granulocytic Anaplasma Immune Evasion Blocking host-cell apoptosis and redirecting Beclin 1-dependent autophagy help infected cells remain permissive for intracellular bacterial growth.

Show evidence (2 references)

PMID:20174550 SUPPORT In Vitro

"Ats-1 inhibited etoposide-induced cytochrome c release from mitochondria, PARP cleavage, and apoptosis in mammalian cells, as well as Bax-induced yeast apoptosis."

Shows that Ats-1 suppresses mitochondria-mediated apoptotic execution.

PMID:23197835 SUPPORT In Vitro

"Thus, Anaplasma actively induces autophagy by secreting Ats-1 that hijacks the Beclin 1-Atg14L autophagy initiation pathway likely to acquire host nutrients for its growth."

Establishes Ats-1-driven Beclin 1/Atg14L autophagy induction as a growth support pathway for the intracellular organism.

Msp2(p44) Antigenic Variation

During chronic infection A. phagocytophilum uses gene conversion to shuffle ~100 msp2(p44) pseudogenes into a single expression cassette, continually varying its major surface antigen Msp2 and evading the antibody response.

DNA recombination GO:0006310 ↑ INCREASED antigenic variation GO:0020033 ↑ INCREASED

Downstream

Granulocytic Anaplasma Immune Evasion Continual surface-antigen variation lets the organism escape the serotype-specific antibody response and persist.

Show evidence (1 reference)

PMID:22859615 SUPPORT Model Organism

"A. phagocytophilum utilizes gene conversion to shuffle approximately 100 functional pseudogenes into a single expression cassette of the msp2(p44) gene, which encodes the major surface antigen, major surface protein 2 (Msp2)."

The woodrat reservoir study establishes msp2(p44) gene-conversion antigenic variation as the surface-antigen switching mechanism.

Granulocytic Anaplasma Immune Evasion

Effector-mediated suppression of phagolysosome fusion, respiratory burst, and neutrophil apoptosis lets Anaplasma organisms persist and amplify in the otherwise bactericidal granulocyte.

neutrophil CL:0000775

biological process involved in interaction with host GO:0051701 ↑ INCREASED

Downstream

IFN-gamma-STAT1 Immunopathology Sustained infection elicits cytokine responses that converge on IFN-gamma-associated STAT1 signaling and inflammatory injury.

Acute Febrile Cytopenic HGA Replicating intracellular infection produces the characteristic acute febrile illness with leukopenia, thrombocytopenia, and abnormal hepatic injury tests.

Show evidence (1 reference)

PMID:17275372 SUPPORT REVIEW SYNTHESIS Other

"These include its ability to inhibit phagosome-lysosome fusion, to suppress respiratory burst and to delay the apoptotic death of neutrophils."

Review synthesis of the neutrophil-killing pathways that A. phagocytophilum subverts during intracellular survival.

IFN-gamma-STAT1 Immunopathology

A. phagocytophilum infection drives IFN-gamma-associated STAT1 signaling; phosphorylated STAT1 tracks with inflammatory tissue injury, implicating host cytokine signaling rather than simple bacterial biomass as a driver of severe lesions.

IFN-gamma-mediated signaling pathway GO:0060333 ↑ INCREASED response to IFN-gamma GO:0034341 ↑ INCREASED

Downstream

Acute Febrile Cytopenic HGA IFN-gamma-STAT1 signaling contributes to the immunopathologic inflammatory lesion arm of HGA.

Show evidence (1 reference)

PMID:23278812 SUPPORT Model Organism

"This increase in phosphorylated Stat1 (pStat1) correlated significantly with IFN-gamma production and inflammatory tissue injury."

Mouse infection data link IFN-gamma production, STAT1 phosphorylation, and inflammatory tissue injury during A. phagocytophilum infection.

Acute Febrile Cytopenic HGA

The organism-level acute syndrome presents as an undifferentiated fever with cytopenias and biochemical liver injury; a minority of reported patients develop life-threatening complications such as ARDS or secondary HLH.

Downstream

Fever

Thrombocytopenia

Leukopenia

Elevated Hepatic Transaminases

Headache

Myalgia

Chills

Malaise

Acute Respiratory Distress Syndrome

Acute kidney injury

Multi-organ failure

Hemophagocytosis

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)."

Pooled human literature review identifying the febrile, cytopenic, and hepatic-laboratory syndrome that characterizes HGA.

Anaplasma Ribosomal Translation (Doxycycline Target)

A. phagocytophilum depends on 70S-ribosome translation; doxycycline exploits this vulnerability by binding the 30S ribosomal subunit and arresting bacterial protein synthesis.

translation GO:0006412

Show evidence (1 reference)

PMID:24336183 SUPPORT REVIEW SYNTHESIS Other

"The ribosome is one of the main antibiotic targets in the bacterial cell."

Review synthesis of the bacterial ribosome as an antibiotic target, supporting this conserved therapeutic-vulnerability node.

Cell-Penetrant Antimicrobial Requirement

Because A. phagocytophilum replicates inside granulocytes, treatment must use agents that achieve intracellular concentrations rather than poorly cell-penetrant antibiotics.

response to antibiotic GO:0046677

Show evidence (1 reference)

PMID:28639230 SUPPORT REVIEW SYNTHESIS Other

"Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents."

Review synthesis establishing intracellular drug accumulation as the pharmacologic requirement this HGA node conforms to.

⬡

Pathograph

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Phenotypes

12

Blood 3

Thrombocytopenia FREQUENT HP:0001873

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)."

The systematic review found thrombocytopenia in 71.8% of HGA cases, within the 30-79% frequent band.

Leukopenia FREQUENT Decreased total leukocyte count HP:0001882

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)."

The systematic review found leukopenia in 49.8% of HGA cases, within the 30-79% frequent band.

Hemophagocytosis RARE HP:0012156

Show evidence (1 reference)

PMID:32723647 SUPPORT Human Clinical

"We present two cases of severe anaplasmosis that progressed to secondary hemophagocytic lymphohistiocytosis (HLH)."

Case-series evidence documents severe anaplasmosis progressing to secondary HLH, whose defining histologic process is hemophagocytosis.

Genitourinary 1

Acute kidney injury OCCASIONAL HP:0001919

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"acute renal failure 9.8%, multi organ failure 7.5%, ARDS"

The systematic review reports acute renal failure in 9.8% of HGA cases.

Immune 1

Acute Respiratory Distress Syndrome OCCASIONAL HP:0033677

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"Although we found complications reported in a total of 40.5% of the reviewed cases and severe and even life-threatening complications are not infrequent (e.g. acute renal failure 9.8%, multi organ failure 7.5%, ARDS 6.3%, a.o.), sequelae are rare (2.1% of the cases) and lethality is low (3.0% of..."

The systematic review found ARDS in 6.3% of HGA cases, within the 5-29% occasional band.

Metabolism 2

Fever VERY_FREQUENT HP:0001945

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)."

The systematic review found fever in 88.5% of HGA cases, supporting a very-frequent fever phenotype.

Elevated Hepatic Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"HGA primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)."

The systematic review found abnormal liver injury tests in 66.7% of HGA cases; elevated circulating hepatic transaminases are the HPO-bound laboratory abnormality represented by that clinical phrasing.

Nervous System 1

Headache FREQUENT HP:0002315

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"The fever is accompanied by unspecific symptoms like weakness, malaise, headache, myalgia, arthralgia, nausea, and vomiting and rarely a rash is present."

The systematic review lists headache among the common unspecific symptoms accompanying HGA fever.

Constitutional 3

Myalgia FREQUENT HP:0003326

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"The fever is accompanied by unspecific symptoms like weakness, malaise, headache, myalgia, arthralgia, nausea, and vomiting and rarely a rash is present."

The systematic review lists myalgia among the common unspecific symptoms accompanying HGA fever.

Chills FREQUENT HP:0025143

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"The most common symptoms in symptomatic patients include fever, chills, malaise, headache, and myalgia"

The systematic review lists chills among the most common symptoms of symptomatic HGA.

Malaise FREQUENT HP:0033834

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"The most common symptoms in symptomatic patients include fever, chills, malaise, headache, and myalgia"

The systematic review lists malaise among the most common symptoms of symptomatic HGA.

Other 1

Multi-organ failure OCCASIONAL

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"acute renal failure 9.8%, multi organ failure 7.5%, ARDS"

The systematic review reports multi-organ failure in 7.5% of HGA cases; no HPO term exists for this outcome, so no term is bound.

💊

Medical Actions

2

Doxycycline

Action: Pharmacotherapy NCIT:C15986

Agent: doxycycline CHEBI:50845

Platform: Small molecule

First-line tetracycline pharmacotherapy for suspected or confirmed HGA.

Mechanism Target:

INHIBITS Anaplasma Ribosomal Translation (Doxycycline Target) — Doxycycline inhibits the Anaplasma 30S ribosomal subunit, shutting down bacterial protein synthesis.

BYPASSES Cell-Penetrant Antimicrobial Requirement — Doxycycline satisfies the cell-penetrant-drug requirement for an organism that replicates inside granulocytes.

Show evidence (1 reference)

PMID:27172113 SUPPORT Other

"Doxycycline is the drug of choice for treatment of all tickborne rickettsial diseases in patients of all ages, including children aged <8 years"

National recommendations for tickborne rickettsial diseases, ehrlichioses, and anaplasmosis establish doxycycline as first-line cell-penetrant therapy. Evidence source is OTHER as this is a national recommendations report.

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"Treatment with doxycycline shows a rapid response, with the fever subsiding in the majority of patients within one day of starting treatment."

Systematic-review evidence supports doxycycline as an effective HGA pharmacotherapy.

Rifampin During Pregnancy

Action: Pharmacotherapy NCIT:C15986

Agent: rifampin CHEBI:28077

Platform: Small molecule

Rifampin is a reported alternative pharmacotherapy for HGA in pregnancy when tetracycline exposure is avoided.

Show evidence (1 reference)

PMID:17682993 SUPPORT Human Clinical

"Human granulocytic ehrlichiosis did not seem to present in a fulminant fashion, and all treated patients had excellent responses to rifampin or doxycycline therapy."

Pregnancy case-series evidence supports rifampin or doxycycline response in treated pregnant patients with the disease historically called human granulocytic ehrlichiosis.

🔬

Diagnosis

1

Blood PCR and Indirect Immunofluorescence

HGA diagnosis commonly combines acute whole-blood PCR or smear review with indirect immunofluorescence serology.

Show evidence (1 reference)

PMID:20077398 SUPPORT REVIEW SYNTHESIS Other

"The laboratory diagnosis is most frequently serological--evidence of antibody by indirect immunofluorescence assay (IFA) and detection of DNA by polymerase chain reaction (PCR), or microscopy evidence--Giemsa stain of blood smears (morulae in granulocytes or monocytes)."

Review synthesis identifying IFA serology, PCR, and Giemsa smear detection of morulae as common HGA diagnostic routes.

📊

Prevalence

1

United States (national surveillance, 2008-2012)

Annual Incidence 0.727 per 100,000 per year 1–9 per 1,000,000 per year

A calculated US incidence of 7.27 cases per million population per year for 2008-2012, a fivefold increase over 2000-2007.

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"a calculated incidence rate of 7.27 cases per million population was reported"

US surveillance incidence of HGA for 2008-2012, cases per million population per year.

🦠

Infectious Agent

1

Anaplasma phagocytophilum

Obligate intracellular Anaplasmataceae bacterium with tropism for human granulocytes.

Anaplasma phagocytophilum NCBITaxon:948

Show evidence (1 reference)

PMID:39102427 SUPPORT Human Clinical

"Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne bacterial infection caused by Anaplasma phagocytophilum."

Establishes A. phagocytophilum as the bacterial agent of human HGA.

↔️

Transmission

3

Ixodes Tick Bite Transmission

HGA is transmitted through the bite of infected Ixodes ticks, including I. scapularis and I. pacificus in the United States.

Show evidence (1 reference)

PMID:20077398 SUPPORT REVIEW SYNTHESIS Other

"These agents are transmitted through the bite of infected tick. In the United States, the vectors are Amblyomma americanum, Ixodes scapularis and Ixodes pacificus ticks."

Review synthesis identifying infected tick bites as the route and naming I. scapularis and I. pacificus among United States Anaplasmataceae vectors.

Transfusion-Associated Transmission

Blood transfusion is a rare non-vector route of A. phagocytophilum acquisition.

Show evidence (1 reference)

PMID:25385549 SUPPORT Human Clinical

"Although usually transmitted via tick bite, HGA may rarely also be acquired through transfusion."

Case-report evidence documents transfusion-associated HGA as a rare acquisition route.

Perinatal Transmission

Perinatal transmission can occur but is rare.

Show evidence (1 reference)

PMID:17682993 SUPPORT Human Clinical

"Perinatal transmission was documented in 1 neonate, who responded well to treatment."

Case-series evidence documents perinatal HGA transmission in one neonate.

{ }

Source YAML

click to show

name: Human Granulocytic Anaplasmosis
creation_date: "2026-09-25T09:44:24Z"
category: Infectious Disease
parents:
- Tick-borne disease
- Anaplasmataceae infectious disease
synonyms:
- HGA
- Human granulocytic ehrlichiosis
- Human granulocytotropic anaplasmosis
description: >-
  Human granulocytic anaplasmosis is an acute Ixodes tick-borne bacterial
  infection caused by the obligate intracellular bacterium Anaplasma
  phagocytophilum. The organism enters neutrophils, remodels host antimicrobial
  and survival programs with type IV secretion effectors, and produces a
  nonspecific febrile illness often accompanied by leukopenia, thrombocytopenia,
  and abnormal hepatic injury tests.
disease_term:
  preferred_term: human granulocytic anaplasmosis
  term:
    id: MONDO:0005118
    label: human granulocytic anaplasmosis
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:39102427
      reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne
        bacterial infection caused by Anaplasma phagocytophilum.
      explanation: >-
        The systematic review defines HGA as a tick-borne bacterial infection,
        supporting placement under Harrison's infectious-diseases part.
pathophysiology:
- name: Ixodes-Borne Anaplasma Inoculation
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Infected Ixodes ticks inoculate A. phagocytophilum and initiate the
    granulocytic intracellular infection that defines HGA.
  biological_processes:
  - preferred_term: symbiont entry into host
    term:
      id: GO:0044409
      label: symbiont entry into host
  downstream:
  - target: PSGL-1-Mediated Neutrophil Entry
    causal_link_type: DIRECT
    description: >-
      Tick inoculation delivers organisms that then bind granulocyte receptors
      and enter neutrophils.
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne
      bacterial infection caused by Anaplasma phagocytophilum.
    explanation: >-
      Establishes tick-borne A. phagocytophilum infection as the initiating
      exposure for HGA.

- name: PSGL-1-Mediated Neutrophil Entry
  biological_scale: CELLULAR
  description: >-
    A. phagocytophilum engages granulocyte receptors including PSGL-1 and its
    sialyl Lewis x cap to enter neutrophils and deliver effector cargo.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  downstream:
  - target: Anaplasma-Occupied Granulocyte Inclusion
    causal_link_type: DIRECT
    description: >-
      Receptor-dependent entry seeds the intracellular inclusion in which the
      bacterium can survive.
  evidence:
  - reference: PMID:18485118
    reference_title: "Anaplasma phagocytophilum PSGL-1-independent infection does not require Syk and leads to less efficient AnkA delivery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      P-selectin glycoprotein ligand-1 (PSGL-1) and the tetrasaccharide sialyl
      Lewis x (sLe(x)), which caps the PSGL-1 N-terminus, are confirmed A.
      phagocytophilum receptors.
    explanation: >-
      Identifies PSGL-1 and sialyl Lewis x as host receptors used by A.
      phagocytophilum during granulocytic infection.

- name: Anaplasma-Occupied Granulocyte Inclusion
  biological_scale: CELLULAR
  description: >-
    The bacterium multiplies in granulocytes inside a protected inclusion, a
    niche that separates the organism from extracellular immune effectors and
    underlies the need for cell-penetrant therapy.
  role: intrinsic_resistance
  conforms_to: >-
    intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam
    Exclusion
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  downstream:
  - target: AnkA-Driven NADPH Oxidase Silencing
    causal_link_type: DIRECT
    description: >-
      Intracellular organisms use a type IV secretion system to deliver AnkA
      into the host nucleus.
  - target: Ats-1 Anti-Apoptosis and Autophagy Hijacking
    causal_link_type: DIRECT
    description: >-
      Intracellular organisms deliver Ats-1 to mitochondria and autophagy
      initiation machinery.
  - target: Anaplasma Ribosomal Translation (Doxycycline Target)
    description: >-
      Intracellular Anaplasma remains dependent on its bacterial ribosome for
      protein synthesis.
  - target: Msp2(p44) Antigenic Variation
    causal_link_type: DIRECT
    description: >-
      Persistent intracellular organisms shuffle msp2(p44) pseudogenes to vary
      their major surface antigen.
  evidence:
  - reference: PMID:17275372
    reference_title: "Immune evasion and immunosuppression by Anaplasma phagocytophilum, the causative agent of tick-borne fever of ruminants and human granulocytic anaplasmosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Anaplasma phagocytophilum, the causative agent of tick-borne fever (TBF)
      in sheep and cattle and human granulocytic anaplasmosis, has the unique
      ability to infect and multiply within neutrophils, eosinophils and
      monocytes, cells at the frontline of the immune system.
    explanation: >-
      Review synthesis establishing multiplication of A. phagocytophilum in
      granulocytic host cells.

- name: AnkA-Driven NADPH Oxidase Silencing
  biological_scale: MOLECULAR
  description: >-
    The type IV secretion effector AnkA traffics into the granulocyte nucleus,
    binds AT-rich DNA at antimicrobial defense genes, recruits HDAC1 at the CYBB
    promoter, and represses NADPH oxidase expression, reducing respiratory-burst
    killing.
  biological_processes:
  - preferred_term: negative regulation of respiratory burst
    modifier: INCREASED
    term:
      id: GO:0060268
      label: negative regulation of respiratory burst
  downstream:
  - target: Granulocytic Anaplasma Immune Evasion
    causal_link_type: DIRECT
    description: >-
      Silencing CYBB suppresses the NADPH-oxidase component of neutrophil
      oxidative killing and helps intracellular organisms avoid bactericidal
      attack.
  evidence:
  - reference: PMID:25996657
    reference_title: "Chromatin-bound bacterial effector ankyrin A recruits histone deacetylase 1 and modifies host gene expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ankyrin A (AnkA), an A. phagocytophilum type IV secretion system
      effector, enters the granulocyte nucleus, binds stretches of AT-rich DNA
      and alters transcription of antimicrobial defence genes, including
      down-regulation of CYBB.
    explanation: >-
      Establishes the nuclear AnkA effector and its repression of the CYBB
      NADPH-oxidase gene in granulocytes.
  - reference: PMID:25996657
    reference_title: "Chromatin-bound bacterial effector ankyrin A recruits histone deacetylase 1 and modifies host gene expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, a direct interaction between AnkA and HDAC1 was detected at
      the CYBB promoter, and was critical for AnkA-mediated CYBB repression.
    explanation: >-
      Links AnkA recruitment of HDAC1 at the CYBB promoter to the silencing of
      the neutrophil oxidative-burst gene.

- name: Ats-1 Anti-Apoptosis and Autophagy Hijacking
  biological_scale: CELLULAR
  description: >-
    The A. phagocytophilum Ats-1 effector enters host mitochondria to suppress
    intrinsic apoptosis and also binds Beclin 1/Atg14L to nucleate autophagosomes
    that support the Anaplasma inclusion.
  biological_processes:
  - preferred_term: negative regulation of apoptotic process
    modifier: INCREASED
    term:
      id: GO:0043066
      label: negative regulation of apoptotic process
  - preferred_term: autophagosome assembly
    modifier: INCREASED
    term:
      id: GO:0000045
      label: autophagosome assembly
  downstream:
  - target: Granulocytic Anaplasma Immune Evasion
    causal_link_type: DIRECT
    description: >-
      Blocking host-cell apoptosis and redirecting Beclin 1-dependent autophagy
      help infected cells remain permissive for intracellular bacterial growth.
  evidence:
  - reference: PMID:20174550
    reference_title: "Anaplasma phagocytophilum Ats-1 is imported into host cell mitochondria and interferes with apoptosis induction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ats-1 inhibited etoposide-induced cytochrome c release from mitochondria,
      PARP cleavage, and apoptosis in mammalian cells, as well as Bax-induced
      yeast apoptosis.
    explanation: >-
      Shows that Ats-1 suppresses mitochondria-mediated apoptotic execution.
  - reference: PMID:23197835
    reference_title: "Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, Anaplasma actively induces autophagy by secreting Ats-1 that
      hijacks the Beclin 1-Atg14L autophagy initiation pathway likely to acquire
      host nutrients for its growth.
    explanation: >-
      Establishes Ats-1-driven Beclin 1/Atg14L autophagy induction as a growth
      support pathway for the intracellular organism.

- name: Msp2(p44) Antigenic Variation
  biological_scale: MOLECULAR
  description: >-
    During chronic infection A. phagocytophilum uses gene conversion to shuffle
    ~100 msp2(p44) pseudogenes into a single expression cassette, continually
    varying its major surface antigen Msp2 and evading the antibody response.
  biological_processes:
  - preferred_term: DNA recombination
    modifier: INCREASED
    term:
      id: GO:0006310
      label: DNA recombination
  - preferred_term: antigenic variation
    modifier: INCREASED
    term:
      id: GO:0020033
      label: antigenic variation
  downstream:
  - target: Granulocytic Anaplasma Immune Evasion
    causal_link_type: DIRECT
    description: >-
      Continual surface-antigen variation lets the organism escape the
      serotype-specific antibody response and persist.
  evidence:
  - reference: PMID:22859615
    reference_title: Antigen variability in Anaplasma phagocytophilum during chronic infection of a reservoir host.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A. phagocytophilum utilizes gene conversion to shuffle approximately 100 functional pseudogenes into a single expression cassette of the msp2(p44) gene, which encodes the major surface antigen, major surface protein 2 (Msp2)."
    explanation: >-
      The woodrat reservoir study establishes msp2(p44) gene-conversion antigenic
      variation as the surface-antigen switching mechanism.
- name: Granulocytic Anaplasma Immune Evasion
  biological_scale: CELLULAR
  description: >-
    Effector-mediated suppression of phagolysosome fusion, respiratory burst,
    and neutrophil apoptosis lets Anaplasma organisms persist and amplify in the
    otherwise bactericidal granulocyte.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: biological process involved in interaction with host
    modifier: INCREASED
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  downstream:
  - target: IFN-gamma-STAT1 Immunopathology
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained infection elicits cytokine responses that converge on
      IFN-gamma-associated STAT1 signaling and inflammatory injury.
  - target: Acute Febrile Cytopenic HGA
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Replicating intracellular infection produces the characteristic acute
      febrile illness with leukopenia, thrombocytopenia, and abnormal hepatic
      injury tests.
  evidence:
  - reference: PMID:17275372
    reference_title: "Immune evasion and immunosuppression by Anaplasma phagocytophilum, the causative agent of tick-borne fever of ruminants and human granulocytic anaplasmosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These include its ability to inhibit phagosome-lysosome fusion, to
      suppress respiratory burst and to delay the apoptotic death of
      neutrophils.
    explanation: >-
      Review synthesis of the neutrophil-killing pathways that A. phagocytophilum
      subverts during intracellular survival.

- name: IFN-gamma-STAT1 Immunopathology
  biological_scale: CELLULAR
  description: >-
    A. phagocytophilum infection drives IFN-gamma-associated STAT1 signaling;
    phosphorylated STAT1 tracks with inflammatory tissue injury, implicating
    host cytokine signaling rather than simple bacterial biomass as a driver of
    severe lesions.
  biological_processes:
  - preferred_term: IFN-gamma-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060333
      label: type II interferon-mediated signaling pathway
  - preferred_term: response to IFN-gamma
    modifier: INCREASED
    term:
      id: GO:0034341
      label: response to type II interferon
  downstream:
  - target: Acute Febrile Cytopenic HGA
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      IFN-gamma-STAT1 signaling contributes to the immunopathologic inflammatory
      lesion arm of HGA.
  evidence:
  - reference: PMID:23278812
    reference_title: "Anaplasma phagocytophilum, interferon gamma production and Stat1 signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This increase in phosphorylated Stat1 (pStat1) correlated significantly
      with IFN-gamma production and inflammatory tissue injury.
    explanation: >-
      Mouse infection data link IFN-gamma production, STAT1 phosphorylation, and
      inflammatory tissue injury during A. phagocytophilum infection.

- name: Acute Febrile Cytopenic HGA
  biological_scale: ORGANISM
  role: outcome
  description: >-
    The organism-level acute syndrome presents as an undifferentiated fever with
    cytopenias and biochemical liver injury; a minority of reported patients
    develop life-threatening complications such as ARDS or secondary HLH.
  downstream:
  - target: Fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Leukopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elevated Hepatic Transaminases
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Headache
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Myalgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chills
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Malaise
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Acute Respiratory Distress Syndrome
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Acute kidney injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Multi-organ failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hemophagocytosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HGA primarily presents as an unspecific febrile illness (88.5% of the
      cases) often accompanied by thrombocytopenia (71.8% of the cases),
      abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8%
      of the cases).
    explanation: >-
      Pooled human literature review identifying the febrile, cytopenic, and
      hepatic-laboratory syndrome that characterizes HGA.

- name: Anaplasma Ribosomal Translation (Doxycycline Target)
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: >-
    bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the
    Ribosome
  description: >-
    A. phagocytophilum depends on 70S-ribosome translation; doxycycline exploits
    this vulnerability by binding the 30S ribosomal subunit and arresting
    bacterial protein synthesis.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
  evidence:
  - reference: PMID:24336183
    reference_title: "Ribosome-targeting antibiotics and mechanisms of bacterial resistance."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Review synthesis of the bacterial ribosome as an antibiotic target,
      supporting this conserved therapeutic-vulnerability node.

- name: Cell-Penetrant Antimicrobial Requirement
  biological_scale: CELLULAR
  role: therapeutic_vulnerability
  conforms_to: >-
    intracellular_pathogen_persistence#Requirement for Cell-Penetrant
    Antimicrobials
  description: >-
    Because A. phagocytophilum replicates inside granulocytes, treatment must
    use agents that achieve intracellular concentrations rather than poorly
    cell-penetrant antibiotics.
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:28639230
    reference_title: "Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Therapeutic efficacy against intracellular pathogens has been correlated
      mainly with the intracellular concentrations achieved by the different
      antimicrobial agents.
    explanation: >-
      Review synthesis establishing intracellular drug accumulation as the
      pharmacologic requirement this HGA node conforms to.
phenotypes:
- name: Fever
  description: >-
    Fever is the dominant presentation of HGA, reported in 88.5% of reviewed
    cases.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HGA primarily presents as an unspecific febrile illness (88.5% of the
      cases) often accompanied by thrombocytopenia (71.8% of the cases),
      abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8%
      of the cases).
    explanation: >-
      The systematic review found fever in 88.5% of HGA cases, supporting a
      very-frequent fever phenotype.

- name: Thrombocytopenia
  description: >-
    Thrombocytopenia is a frequent hematologic abnormality in HGA and was
    present in 71.8% of reviewed cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HGA primarily presents as an unspecific febrile illness (88.5% of the
      cases) often accompanied by thrombocytopenia (71.8% of the cases),
      abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8%
      of the cases).
    explanation: >-
      The systematic review found thrombocytopenia in 71.8% of HGA cases,
      within the 30-79% frequent band.

- name: Leukopenia
  description: >-
    Leukopenia is frequent in HGA and was reported in 49.8% of reviewed cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HGA primarily presents as an unspecific febrile illness (88.5% of the
      cases) often accompanied by thrombocytopenia (71.8% of the cases),
      abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8%
      of the cases).
    explanation: >-
      The systematic review found leukopenia in 49.8% of HGA cases, within the
      30-79% frequent band.

- name: Elevated Hepatic Transaminases
  description: >-
    Abnormal hepatic injury tests are frequent in HGA; the HPO binding captures
    the common elevated-transaminase manifestation of this laboratory
    abnormality.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HGA primarily presents as an unspecific febrile illness (88.5% of the
      cases) often accompanied by thrombocytopenia (71.8% of the cases),
      abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8%
      of the cases).
    explanation: >-
      The systematic review found abnormal liver injury tests in 66.7% of HGA
      cases; elevated circulating hepatic transaminases are the HPO-bound
      laboratory abnormality represented by that clinical phrasing.

- name: Acute Respiratory Distress Syndrome
  description: >-
    ARDS is an occasional severe complication of HGA, reported in 6.3% of the
    reviewed cases.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although we found complications reported in a total of 40.5% of the
      reviewed cases and severe and even life-threatening complications are not
      infrequent (e.g. acute renal failure 9.8%, multi organ failure 7.5%, ARDS
      6.3%, a.o.), sequelae are rare (2.1% of the cases) and lethality is low
      (3.0% of the cases).
    explanation: >-
      The systematic review found ARDS in 6.3% of HGA cases, within the 5-29%
      occasional band.

- name: Headache
  description: Headache is a common accompanying symptom of the acute HGA febrile illness.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fever is accompanied by unspecific symptoms like weakness, malaise, headache, myalgia, arthralgia, nausea, and vomiting and rarely a rash is present."
    explanation: The systematic review lists headache among the common unspecific symptoms accompanying HGA fever.
- name: Myalgia
  description: Myalgia is a common accompanying symptom of the acute HGA febrile illness.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fever is accompanied by unspecific symptoms like weakness, malaise, headache, myalgia, arthralgia, nausea, and vomiting and rarely a rash is present."
    explanation: The systematic review lists myalgia among the common unspecific symptoms accompanying HGA fever.
- name: Chills
  description: Chills are among the most common presenting symptoms of HGA.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chills
    term:
      id: HP:0025143
      label: Chills
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptoms in symptomatic patients include fever, chills, malaise, headache, and myalgia"
    explanation: The systematic review lists chills among the most common symptoms of symptomatic HGA.
- name: Malaise
  description: Malaise is a common accompanying symptom of the acute HGA febrile illness.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Malaise
    term:
      id: HP:0033834
      label: Malaise
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptoms in symptomatic patients include fever, chills, malaise, headache, and myalgia"
    explanation: The systematic review lists malaise among the most common symptoms of symptomatic HGA.
- name: Acute kidney injury
  description: Acute renal failure is an occasional severe complication of HGA, reported in 9.8% of reviewed cases.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute renal failure 9.8%, multi organ failure 7.5%, ARDS"
    explanation: The systematic review reports acute renal failure in 9.8% of HGA cases.
- name: Multi-organ failure
  description: Multi-organ failure is a severe complication of HGA, reported in 7.5% of reviewed cases.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Multi-organ failure
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acute renal failure 9.8%, multi organ failure 7.5%, ARDS"
    explanation: The systematic review reports multi-organ failure in 7.5% of HGA cases; no HPO term exists for this outcome, so no term is bound.
- name: Hemophagocytosis
  description: >-
    Severe HGA can trigger secondary hemophagocytic lymphohistiocytosis.
  frequency: RARE
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:32723647
    reference_title: "Severe anaplasmosis represents a treatable cause of secondary hemophagocytic lymphohistiocytosis: Two cases and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present two cases of severe anaplasmosis that progressed to secondary
      hemophagocytic lymphohistiocytosis (HLH).
    explanation: >-
      Case-series evidence documents severe anaplasmosis progressing to
      secondary HLH, whose defining histologic process is hemophagocytosis.
infectious_agent:
- name: Anaplasma phagocytophilum
  description: >-
    Obligate intracellular Anaplasmataceae bacterium with tropism for human
    granulocytes.
  infectious_agent_term:
    preferred_term: Anaplasma phagocytophilum
    term:
      id: NCBITaxon:948
      label: Anaplasma phagocytophilum
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human granulocytotropic anaplasmosis (HGA) is a zoonotic tick-borne
      bacterial infection caused by Anaplasma phagocytophilum.
    explanation: >-
      Establishes A. phagocytophilum as the bacterial agent of human HGA.
transmission:
- name: Ixodes Tick Bite Transmission
  description: >-
    HGA is transmitted through the bite of infected Ixodes ticks, including I.
    scapularis and I. pacificus in the United States.
  evidence:
  - reference: PMID:20077398
    reference_title: "[Ehrlichiosis/Anaplasmosis]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These agents are transmitted through the bite of infected tick. In the
      United States, the vectors are Amblyomma americanum, Ixodes scapularis and
      Ixodes pacificus ticks.
    explanation: >-
      Review synthesis identifying infected tick bites as the route and naming I.
      scapularis and I. pacificus among United States Anaplasmataceae vectors.

- name: Transfusion-Associated Transmission
  description: >-
    Blood transfusion is a rare non-vector route of A. phagocytophilum
    acquisition.
  evidence:
  - reference: PMID:25385549
    reference_title: "Transfusion-associated Anaplasma phagocytophilum infection in a pregnant patient with thalassemia trait: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although usually transmitted via tick bite, HGA may rarely also be
      acquired through transfusion.
    explanation: >-
      Case-report evidence documents transfusion-associated HGA as a rare
      acquisition route.

- name: Perinatal Transmission
  description: >-
    Perinatal transmission can occur but is rare.
  evidence:
  - reference: PMID:17682993
    reference_title: "Human granulocytic anaplasmosis during pregnancy: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Perinatal transmission was documented in 1 neonate, who responded well to
      treatment.
    explanation: >-
      Case-series evidence documents perinatal HGA transmission in one neonate.
diagnosis:
- name: Blood PCR and Indirect Immunofluorescence
  description: >-
    HGA diagnosis commonly combines acute whole-blood PCR or smear review with
    indirect immunofluorescence serology.
  evidence:
  - reference: PMID:20077398
    reference_title: "[Ehrlichiosis/Anaplasmosis]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The laboratory diagnosis is most frequently serological--evidence of
      antibody by indirect immunofluorescence assay (IFA) and detection of DNA
      by polymerase chain reaction (PCR), or microscopy evidence--Giemsa stain
      of blood smears (morulae in granulocytes or monocytes).
    explanation: >-
      Review synthesis identifying IFA serology, PCR, and Giemsa smear detection
      of morulae as common HGA diagnostic routes.
prevalence:
- population: United States (national surveillance, 2008-2012)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.727
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    A calculated US incidence of 7.27 cases per million population per year for
    2008-2012, a fivefold increase over 2000-2007.
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a calculated incidence rate of 7.27 cases per million population was reported"
    explanation: US surveillance incidence of HGA for 2008-2012, cases per million population per year.
treatments:
- name: Doxycycline
  description: >-
    First-line tetracycline pharmacotherapy for suspected or confirmed HGA.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
  target_mechanisms:
  - target: Anaplasma Ribosomal Translation (Doxycycline Target)
    treatment_effect: INHIBITS
    description: >-
      Doxycycline inhibits the Anaplasma 30S ribosomal subunit, shutting down
      bacterial protein synthesis.
  - target: Cell-Penetrant Antimicrobial Requirement
    treatment_effect: BYPASSES
    description: >-
      Doxycycline satisfies the cell-penetrant-drug requirement for an organism
      that replicates inside granulocytes.
    evidence:
    - reference: PMID:27172113
      reference_title: "Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Doxycycline is the drug of choice for treatment of all tickborne
        rickettsial diseases in patients of all ages, including children aged <8
        years
      explanation: >-
        National recommendations for tickborne rickettsial diseases,
        ehrlichioses, and anaplasmosis establish doxycycline as first-line
        cell-penetrant therapy. Evidence source is OTHER as this is a national
        recommendations report.
  evidence:
  - reference: PMID:39102427
    reference_title: "Human granulocytotropic anaplasmosis-A systematic review and analysis of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with doxycycline shows a rapid response, with the fever
      subsiding in the majority of patients within one day of starting
      treatment.
    explanation: >-
      Systematic-review evidence supports doxycycline as an effective HGA
      pharmacotherapy.

- name: Rifampin During Pregnancy
  description: >-
    Rifampin is a reported alternative pharmacotherapy for HGA in pregnancy when
    tetracycline exposure is avoided.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rifampin
      term:
        id: CHEBI:28077
        label: rifampicin
  evidence:
  - reference: PMID:17682993
    reference_title: "Human granulocytic anaplasmosis during pregnancy: case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human granulocytic ehrlichiosis did not seem to present in a fulminant
      fashion, and all treated patients had excellent responses to rifampin or
      doxycycline therapy.
    explanation: >-
      Pregnancy case-series evidence supports rifampin or doxycycline response
      in treated pregnant patients with the disease historically called human
      granulocytic ehrlichiosis.

📚

References & Deep Research

Deep Research

1

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OpenScientist ▸

Human Granulocytic Anaplasmosis (HGA): Comprehensive Disease Characterization Report

openscientist-autonomous 20 citations 2026-09-25T03:02:16.125005

Human Granulocytic Anaplasmosis (HGA): Comprehensive Disease Characterization Report

Target Disease: Human Granulocytic Anaplasmosis MONDO ID: MONDO:0005118 Category: Infectious Disease (tick-borne zoonotic bacterial infection) Causative Agent: Anaplasma phagocytophilum (human-active "Ap-ha" variant), NCBI Taxonomy ID: 948

Summary

Human granulocytic anaplasmosis (HGA) is an acute, usually self-limiting tick-borne febrile illness caused by the obligate intracellular gram-negative bacterium Anaplasma phagocytophilum. It is transmitted principally by Ixodes scapularis (eastern/midwestern United States) and Ixodes pacificus (western United States), with small mammals — chiefly the white-footed mouse Peromyscus leucopus — serving as enzootic reservoirs. Only a single "human active" (Ap-ha) genetic variant of the bacterium causes human disease. HGA is fundamentally an infectious disease with no human genetic etiology: there are no causal genes, inheritance patterns, pathogenic germline variants, or vaccines. The dominant human "risk factors" are environmental and behavioral (tick exposure in endemic regions), with advanced age and immunosuppression predicting severe disease.

The pathogen has a unique biology: it is one of the few bacteria that survives and replicates inside neutrophils, the body's primary antibacterial effector cells. It accomplishes this through an elaborate program of subversion — entering via the PSGL-1/sialyl-Lewis^x receptor complex, then deploying Type IV secretion system (T4SS) effectors AnkA (which epigenetically silences the NADPH-oxidase gene CYBB via HDAC1 recruitment, blocking the respiratory burst) and Ats-1 (which enters host mitochondria to block apoptosis and hijacks autophagy for nutrient acquisition). Crucially, the tissue injury and clinical severity of HGA are driven not by direct bacterial cytotoxicity — bacterial burdens are low relative to disease severity — but by the host immune response, specifically an IFN-γ/STAT1-driven immunopathology. In its most extreme form this dysregulation manifests as secondary hemophagocytic lymphohistiocytosis (HLH).

Clinically, HGA presents as a nonspecific febrile illness (fever in 88.5% of cases) accompanied by thrombocytopenia (71.8%), abnormal liver injury tests (66.7%), and leukopenia (49.8%). It is diagnosed by whole-blood PCR and IFA serology, with blood-smear morulae showing low sensitivity in early disease. Doxycycline is rapidly curative first-line therapy for all ages, with fever typically subsiding within one day; rifampin is the alternative in pregnancy. Prognosis is generally good (lethality ~3.0%, sequelae ~2.1%), though complications occur in ~40% of cases and advanced age plus immunosuppression predict severe/hospitalized disease. Prevention rests entirely on tick-bite avoidance, as no vaccine exists. The same bacterium naturally infects horses, dogs, cats, sheep, cattle, and goats, making HGA part of a broader multi-host zoonosis with important veterinary parallels.

Key Findings

Finding 1: HGA is a tick-borne infection of neutrophils presenting as a febrile illness with cytopenias

A systematic review of HGA cases established the core clinical and laboratory phenotype. HGA "primarily presents as an unspecific febrile illness (88.5% of the cases) often accompanied by thrombocytopenia (71.8% of the cases), abnormal liver injury tests (66.7% of the cases), and leukopenia (49.8% of the cases)" (PMID: 39102427). Complications occurred in 40.5% of cases (acute renal failure 9.8%, multi-organ failure 7.5%, ARDS 6.3%), while "sequelae are rare (2.1% of the cases) and lethality is low (3.0% of the cases)."

This phenotypic signature — fever plus the triad of thrombocytopenia, transaminitis, and leukopenia — is the diagnostic fingerprint of HGA and reflects the pathogen's tropism for hematopoietic and granulocytic lineages. The nonspecific nature of the presentation is a central clinical challenge, since it overlaps with many other acute febrile illnesses and other tick-borne diseases (Lyme disease, babesiosis, ehrlichiosis).

Suggested HPO terms: Fever (HP:0001945), Thrombocytopenia (HP:0001873), Elevated hepatic transaminase (HP:0002910), Leukopenia (HP:0001882), Myalgia (HP:0003326), Headache (HP:0002315), Acute kidney injury (HP:0001919).

Finding 2: A. phagocytophilum survives in neutrophils by subverting bactericidal functions and delaying apoptosis

The paradox of HGA is that the pathogen thrives inside the very cell type designed to destroy it. The bacterium "infects and actively grows in neutrophils by employing an array of mechanisms to subvert their bactericidal activity. These include its ability to inhibit phagosome-lysosome fusion, to suppress respiratory burst and to delay the apoptotic death of neutrophils" (PMID: 17275372).

An Affymetrix microarray study of infected human polymorphonuclear leukocytes (PMNs) demonstrated the apoptosis-evasion mechanism directly: "ingestion of A. phagocytophilum failed to trigger the neutrophil apoptosis differentiation program that typically follows phagocytosis and ROS production" (PMID: 15879137). Normally, neutrophils undergo a programmed apoptotic death shortly after phagocytosis; by suppressing this program, the bacterium extends the lifespan of its intracellular niche, buying time for replication.

Suggested GO terms: negative regulation of apoptotic process (GO:0043066), negative regulation of respiratory burst (GO:0060264), phagosome-lysosome fusion (GO:0090385). Suggested CL term: neutrophil (CL:0000775).

Finding 3: Type IV secretion effectors AnkA and Ats-1 drive intracellular subversion

The molecular machinery of subversion is the T4SS and its two best-characterized effectors. AnkA (Ankyrin A) "enters the granulocyte nucleus, binds stretches of AT-rich DNA and alters transcription of antimicrobial defence genes, including down-regulation of CYBB" (PMID: 25996657). AnkA recruits histone deacetylase 1 (HDAC1) to the CYBB (gp91phox/NADPH oxidase) promoter, causing histone H3 deacetylation and epigenetic silencing — directly disabling the enzyme responsible for the neutrophil respiratory burst. This is a striking example of a bacterial effector functioning as a host transcriptional/epigenetic regulator.

Ats-1 (Anaplasma translocated substrate 1) operates at the mitochondria: it "inhibited etoposide-induced cytochrome c release from mitochondria, PARP cleavage, and apoptosis in mammalian cells" (PMID: 20174550). Ats-1 additionally hijacks autophagy: it "binds Beclin 1, a subunit of the class III PI3K and Atg14L, and it nucleates autophagosomes" (PMID: 23197835), redirecting autophagosomal cargo to feed the bacterium. Multi-omics work further shows Ats-1 up-regulates respiratory-chain subunits (NDUFB5, NDUFB3, NDUFS7, COX6C, SLC25A5), enhancing host ATP production and inhibiting apoptosis to support bacterial replication.

Suggested GO terms: modulation by symbiont of host process (GO:0044003), negative regulation of host apoptotic process, autophagosome assembly (GO:0000045), histone deacetylation (GO:0016575).

Finding 4: Doxycycline is highly effective; advanced age and immunosuppression predict severe disease

"Treatment with doxycycline shows a rapid response, with the fever subsiding in the majority of patients within one day of starting treatment" (PMID: 39102427). This rapid defervescence is so characteristic that a prompt response to empiric doxycycline supports the diagnosis.

Prognostic stratification comes from a 465-case Mayo Clinic cohort (2011–2021), in which 33% of patients were hospitalized. "Hospitalized patients (n = 153, 33%) were more likely to be older (median age of 71 vs 61; P ≤ .001) and immunocompromised (17% vs 7%; P ≤ .001)" (PMID: 40176262). Additional risk factors for hospitalization included altered mental status, higher absolute neutrophil count, and comorbidities. Notably, coinfection (e.g., with Borrelia burgdorferi or Babesia microti) did not impact mortality or hospitalization in this cohort.

Suggested NCIT term: Doxycycline (NCIT:C731).

Finding 5: Entry via PSGL-1/sialyl-Lewis^x and persistence via msp2(p44) antigenic variation

The molecular entry mechanism is well defined: "P-selectin glycoprotein ligand-1 (PSGL-1) and the tetrasaccharide sialyl Lewis x (sLe(x)), which caps the PSGL-1 N-terminus, are confirmed A. phagocytophilum receptors" (PMID: 18485118). PSGL-1 N-terminus-mediated entry is Syk-dependent and promotes optimal delivery of the AnkA effector, linking receptor engagement to the downstream subversion program.

Persistence and immune evasion are achieved through antigenic variation of the immunodominant major surface protein: "A. phagocytophilum utilizes gene conversion to shuffle approximately 100 functional pseudogenes into a single expression cassette of the msp2(p44) gene, which encodes the major surface antigen, major surface protein 2 (Msp2)" (PMID: 22859615). In chronically infected reservoir woodrats, 60 unique expression-site variants emerged over the course of infection — a continuously moving antigenic target that frustrates the antibody response.

Finding 6: HGA is an emerging Ixodes-borne zoonosis; only the Ap-ha variant is human-pathogenic

HGA is transmitted primarily by Ixodes scapularis (eastern/midwestern US) and I. pacificus (western US), with reservoirs in small mammals, chiefly Peromyscus leucopus (white-footed mouse) and eastern chipmunks. Critically, only one variant infects humans: studies reference "the zoonotic variant Ap-ha (human active) of the bacterium Anaplasma phagocytophilum" (PMID: 41016325). Approximately 90–100% of infected reservoir small mammals in southeastern Canada carried Ap-ha.

The disease burden is substantial and rising. US hospitalization data show that "Lyme disease was the most common cause, accounting for 65% of hospitalizations (171,328 admissions), followed by ehrlichiosis/anaplasmosis (46,446)" over 2002–2021 (PMID: 41003548), with tick-borne disease hospitalizations increasing 2.5-fold. The burden concentrates in the Northeast (52.9% of TBD hospitalizations), peaks in July, and affects males slightly more (53.9%). Rare non-tick transmission occurs: "Although usually transmitted via tick bite, HGA may rarely also be acquired through transfusion" (PMID: 25385549) — and leukoreduction does not reliably prevent transfusion transmission — as well as perinatally.

Finding 7: HGA tissue injury is immunopathologic, driven by IFN-γ/STAT1 signaling

A defining and mechanistically important feature of HGA is that disease severity is disproportionate to bacterial burden, pointing to an immune-mediated pathology. "IFN-γ, is necessary for innate immunity and plays an important role in the induction of severe histopathology in A. phagocytophilum-infected mice, horses and humans" (PMID: 23278812). The downstream signaling node is STAT1: an "increase in phosphorylated Stat1 (pStat1) correlated significantly with IFN-γ production and inflammatory tissue injury," with phosphorylated STAT1 markedly increased by day 7 post-infection in infected mice.

This immunopathologic model reframes HGA: the pathogen sets off a host inflammatory cascade (via TLR2/NF-κB and IFN-γ/STAT1) that produces the observed organ injury. It is reinforced by the observation, in CNS involvement, that "CSF abnormalities did not correlate with neurologic severity, suggesting a cytokine-mediated process rather than direct central nervous system infection" (PMID: 42230277).

Suggested GO terms: interferon-gamma-mediated signaling pathway (GO:0060333), inflammatory response (GO:0006954), response to interferon-gamma (GO:0034341).

Finding 8: Diagnosis relies on PCR and serology; blood-smear morulae have low early sensitivity

"The laboratory diagnosis is most frequently serological—evidence of antibody by indirect immunofluorescence assay (IFA) and detection of DNA by polymerase chain reaction (PCR), or microscopy evidence—Giemsa stain of blood smears (morulae in granulocytes or monocytes)" (PMID: 20077398). Morulae are intracytoplasmic microcolonies of the bacterium — the pathognomonic but insensitive microscopic finding.

A Korean hospital cohort quantified this insensitivity: "Of the 18 patients who underwent peripheral blood (PB) smear test, only one (5.6%) had morulae" (PMID: 34035378). Because both morulae detection and IFA (which requires seroconversion) are insensitive in early disease, whole-blood PCR is the primary early diagnostic tool, and empiric doxycycline should not await confirmation.

Finding 9: Doxycycline is first-line for all ages; rifampin is the alternative in pregnancy

In a case series of six pregnant women with HGA, disease was non-fulminant and "all treated patients had excellent responses to rifampin or doxycycline therapy. Perinatal transmission was documented in 1 neonate, who responded well to treatment" (PMID: 17682993), with no long-term sequelae in offspring at a mean follow-up of 21 months. A transfusion-associated case in a pregnant patient was successfully treated with rifampin (PMID: 25385549). Doxycycline remains the drug of choice across all systematic reviews and all age groups; rifampin is reserved for pregnancy and doxycycline intolerance.

Suggested NCIT terms: Doxycycline (NCIT:C731), Rifampin (NCIT:C692).

Finding 10: A. phagocytophilum is a multi-host zoonotic pathogen (granulocytic anaplasmosis / tick-borne fever)

The same bacterium causes disease across many mammalian species. Genetic typing (ankA, groEL, MLST) shows "the A. phagocytophilum strains found infecting cats are the same as those that cause disease in humans, dogs and horses" (PMID: 37803346). In naturally PCR-positive horses, hematological abnormalities occurred in 95%, dominated by thrombocytopenia (86%) and anemia (52%) — paralleling the human thrombocytopenia phenotype (PMID: 36436292). In ruminants the disease is called tick-borne fever (TBF): "By itself TBF does not cause high mortality rates but infected animals are more susceptible to other secondary infections, pregnant animals may abort and there is a severe reduction in milk yield in dairy cattle" (PMID: 17275372).

Suggested NCBI Taxonomy identifiers for affected species: Homo sapiens (9606), Equus caballus (9796), Canis lupus familiaris (9615), Felis catus (9685), Ovis aries (9940), Bos taurus (9913), Capra hircus (9925), Peromyscus leucopus (10041).

Finding 11: Severe anaplasmosis can trigger secondary HLH, a treatable immune-dysregulation complication

The immunopathologic model reaches its extreme in secondary HLH. Case reports "present two cases of severe anaplasmosis that progressed to secondary hemophagocytic lymphohistiocytosis (HLH). This severe immune dysregulation syndrome has an extremely high mortality, but anaplasmosis represents one of the few treatable underlying etiologies" (PMID: 32723647). One "anaplasmosis-induced HLH successfully treated with a combination of doxycycline, steroids, and anakinra (an IL-1 receptor antagonist)" — demonstrating that this primarily immune-mediated complication responds to both antimicrobial therapy and immunosuppression, and reinforcing the cytokine-driven mechanism.

Suggested NCIT terms: Anakinra (NCIT:C1594), Corticosteroid therapy. Suggested HPO term: Hemophagocytosis (HP:0012156).

Finding 12: Integrated model — pathogen-driven neutrophil subversion produces host IFN-γ/STAT1 immunopathology, reversible with doxycycline

Synthesizing all findings, HGA follows a coherent causal chain from tick inoculation of the Ap-ha variant to a febrile cytopenic illness that is fully reversible with doxycycline. The upstream arm is pathogen-driven (receptor entry → T4SS effectors → neutrophil subversion); the downstream arm is host-driven (IFN-γ/STAT1 immunopathology → clinical disease, and in extreme cases HLH). Clinically this yields fever (88.5%), thrombocytopenia (71.8%), transaminitis (66.7%), and leukopenia (49.8%) with low lethality (3.0%), and doxycycline produces defervescence within ~1 day. There is no human causal gene, inheritance pattern, or vaccine; prevention is tick-bite avoidance. The two anchoring facts of this synthesis are the clinical output (PMID: 39102427) and the immunopathology driver (PMID: 23278812).

Mechanistic Model / Interpretation

Ordered causal chain (initiating exposure → clinical manifestation)

An Ixodes scapularis or I. pacificus tick carrying the Ap-ha (human-active) variant of A. phagocytophilum bites a human and inoculates the bacterium. (demonstrated — vector/variant epidemiology)
Circulating bacteria bind PSGL-1 capped by sialyl-Lewis^x on neutrophils and myeloid precursors, leading to Syk-dependent internalization into a host-derived vacuole. (demonstrated in vitro)
Internalization results in assembly of the Type IV secretion system and translocation of effectors into the host cell. (demonstrated)
AnkA traffics to the nucleus, binds AT-rich DNA at the CYBB promoter, and recruits HDAC1, causing histone H3 deacetylation and epigenetic silencing of CYBB (gp91phox) — this blocks the NADPH-oxidase respiratory burst. (demonstrated)
In parallel, Ats-1 enters host mitochondria and inhibits cytochrome c release and PARP cleavage, blocking apoptosis; it also binds Beclin 1/Atg14L to nucleate autophagosomes and divert nutrients to the bacterium. (demonstrated in vitro/cell models)
Suppressed oxidative killing + delayed apoptosis + nutrient acquisition result in unchecked intracellular bacterial replication and formation of morulae. (demonstrated)
Branch — immune sensing: bacterial ligands engage TLR2 → NF-κB and drive IFN-γ production; IFN-γ signaling leads to STAT1 phosphorylation (pSTAT1). (demonstrated in mouse/comparative models; inferred in humans)
Elevated IFN-γ/pSTAT1 causes inflammatory, immunopathologic tissue injury that is disproportionate to bacterial burden — producing fever, hepatic transaminitis, and organ dysfunction. (demonstrated in animal models; strongly inferred in humans)
Consumption/sequestration and marrow effects result in thrombocytopenia and leukopenia; the febrile cytopenic syndrome is the clinical readout. (demonstrated clinically; mechanism partly inferred)
Extreme branch: in a subset (older/immunocompromised), unchecked cytokine activation leads to secondary HLH. (demonstrated in case reports)
Doxycycline halts bacterial protein synthesis, collapsing the effector-driven subversion and interrupting the cytokine cascade, resulting in defervescence within ~1 day and full recovery in the great majority. (demonstrated clinically)

Schematic

   Ixodes tick (Ap-ha variant)
      │  inoculation
      ▼
   PSGL-1 / sialyl-Lewis^x  ──Syk──►  neutrophil entry
      │
      ▼
       T4SS effector translocation
├── AnkA → nucleus → HDAC1 at CYBB → ✗ respiratory burst
└── Ats-1 → mitochondria → ✗ apoptosis; Beclin1 → autophagy nutrient theft
      │
      ▼
   Intracellular replication (morulae), low total burden
      │
     ┌────────┴─────────────┐
     ▼ (pathogen arm)        ▼ (host arm)
  neutrophil dysfunction   TLR2/NF-κB + IFN-γ → pSTAT1
              │
              ▼
   IMMUNOPATHOLOGY (severity ≫ burden)
              │
┌─────────────────────┼─────────────────────┐
▼                     ▼                     ▼
   fever (88.5%)     thrombocytopenia (71.8%)   transaminitis (66.7%)
     leukopenia (49.8%)          → extreme: HLH
              │
    doxycycline (≤1 day defervescence) → recovery

Upstream vs downstream

Layer	Mechanism	Direction	Evidence type
Vector/variant	Ixodes transmission of Ap-ha	Most upstream	Epidemiology (human)
Entry	PSGL-1/sLe^x/Syk	Upstream	In vitro
Subversion	AnkA (CYBB silencing), Ats-1 (anti-apoptosis, autophagy)	Upstream	In vitro / cell models
Immune sensing	TLR2/NF-κB, IFN-γ/STAT1	Midstream	Mouse/comparative; inferred in human
Immunopathology	Cytokine-driven tissue injury	Downstream	Animal + clinical inference
Clinical	Fever, cytopenias, transaminitis, HLH	Most downstream	Human clinical

Cell types involved (CL): neutrophil (CL:0000775), granulocyte (CL:0000094), monocyte (CL:0000576), macrophage (CL:0000235). Anatomical structures (UBERON): blood (UBERON:0000178), bone marrow (UBERON:0002371), liver (UBERON:0002107), spleen (UBERON:0002106), lung (UBERON:0002048), kidney (UBERON:0002113). Subcellular (GO CC): nucleus (GO:0005634), mitochondrion (GO:0005739), autophagosome (GO:0005776).

Evidence Base

PMID	Title (abbrev.)	Supports finding	Evidence type
39102427	HGA — systematic review	F1, F4, F12 (clinical phenotype, doxycycline, prognosis)	Human clinical (systematic review)
17275372	Immune evasion & immunosuppression by A. phagocytophilum	F2, F10 (neutrophil subversion; ruminant TBF)	Review / in vitro
15879137	Fails to induce apoptosis in human neutrophils	F2 (apoptosis delay)	In vitro (human PMN microarray)
25996657	Chromatin-bound AnkA recruits HDAC1	F3 (AnkA epigenetic silencing)	In vitro / molecular
20174550	Ats-1 imported into mitochondria, blocks apoptosis	F3 (Ats-1 anti-apoptosis)	In vitro
23197835	Autophagosomes induced by bacterial Beclin 1-binding protein	F3 (Ats-1 autophagy hijack)	In vitro
40176262	Trends in anaplasmosis over the past decade	F4 (prognostic risk factors)	Human clinical (465-case cohort)
18485118	PSGL-1-independent infection, Syk, AnkA delivery	F5 (entry receptors)	In vitro
22859615	Antigen variability during chronic reservoir infection	F5 (msp2/p44 antigenic variation)	In vivo (reservoir host)
41016325	Small mammal hosts of zoonotic A. phagocytophilum, Canada	F6 (Ap-ha variant, reservoirs)	Field epidemiology
41003548	Hospitalizations for TBDs in the US 2002–2021	F6 (US burden)	Epidemiology (registry)
25385549	Transfusion-associated infection in pregnancy	F6, F9 (non-vector transmission; rifampin)	Case report
23278812	IFN-γ production and Stat1 signaling	F7, F12 (immunopathology)	Model organism + comparative
42230277	CSF findings in CNS anaplasmosis	F7 (cytokine-mediated, not direct CNS infection)	Human clinical
15122530	TLR2 activation of NF-κB by A. phagocytophilum	F7/F12 (innate sensing branch)	In vitro
20077398	Ehrlichiosis/Anaplasmosis	F8 (diagnostic modalities)	Review
34035378	HGA in a single Korean university hospital	F8 (morulae low sensitivity)	Human clinical cohort
17682993	HGA during pregnancy: case series	F9 (rifampin/doxycycline in pregnancy)	Case series
37803346	Feline granulocytic anaplasmosis, strain typing	F10 (cross-species strains)	Veterinary/molecular
36436292	A. phagocytophilum in German horses	F10 (equine hematologic parallels)	Veterinary retrospective
32723647	Severe anaplasmosis as treatable cause of HLH	F11 (HLH complication)	Case reports + review

Across the evidence base, the clinical phenotype and treatment findings rest on human systematic reviews and cohorts (strong for descriptive epidemiology); the molecular subversion mechanisms rest on robust in vitro and cell-model data; and the immunopathology model is strongest in mouse and comparative (horse) systems and is inferred — though well-supported — in humans by the dissociation between low bacterial burden and disease severity, and by cytokine-mediated CSF findings.

Section-by-Section Knowledge Base Content

1. Disease Information. HGA is an acute tick-borne bacterial infection of neutrophils. Identifiers: MONDO:0005118; MeSH "Anaplasmosis"/"Ehrlichiosis, Human, Granulocytic"; ICD-10 A79.82 (Anaplasmosis); ICD-11 ~1C30.2. No OMIM/Orphanet genetic entry (not a Mendelian disease). Synonyms: human granulocytic ehrlichiosis (HGE, historical), granulocytic anaplasmosis. Information is derived from aggregated disease-level clinical and epidemiological resources, not germline genetics.

2. Etiology. Causal factor is infectious — the Ap-ha variant of A. phagocytophilum. Risk factors are environmental/behavioral: residence or activity in Ixodes-endemic regions (Northeast/Upper Midwest/Pacific US), outdoor exposure in tick season (peak July), advanced age, and immunosuppression (severity). No genetic risk, protective, or gene-environment factors are established in humans.

3. Phenotypes. Fever (88.5%; HP:0001945), thrombocytopenia (71.8%; HP:0001873), transaminitis (66.7%; HP:0002910), leukopenia (49.8%; HP:0001882); myalgia, headache, chills, arthralgia common; complications include acute renal failure (9.8%), multi-organ failure (7.5%), ARDS (6.3%). Rare: subdural hematoma/CNS involvement, pulmonary embolism, HLH. Onset acute; severity mild-to-severe/variable; course self-limited with treatment.

4. Genetic/Molecular Information. Not applicable at the human host level — no causal genes, pathogenic variants, modifier genes, or chromosomal abnormalities. The relevant molecular biology is the pathogen's virulence genes (ankA, ats-1, msp2/p44, T4SS/virB-virD4) and the host genes they target (CYBB/gp91phox silencing; mitochondrial respiratory-chain subunits NDUFB5/NDUFB3/NDUFS7/COX6C/SLC25A5 up-regulated).

5. Environmental Information. Infectious agent: A. phagocytophilum (NCBI Taxon 948). Vectors: Ixodes scapularis, I. pacificus (also I. ricinus in Europe). Reservoirs: Peromyscus leucopus, chipmunks, other small mammals. Transmission mainly by tick bite; rare via blood transfusion and perinatally.

6. Mechanism/Pathophysiology. See the ordered causal chain and schematic above. Molecular pathways: TLR2/NF-κB, IFN-γ/JAK-STAT1; host NADPH-oxidase pathway (silenced); mitochondrial apoptosis and autophagy (subverted). Immune involvement is central and immunopathologic.

7. Anatomical Structures Affected. Primary: blood/hematopoietic system (neutrophils; UBERON:0000178, bone marrow UBERON:0002371). Secondary: liver (UBERON:0002107), spleen, kidney, lung, occasionally CNS. Subcellular: host cytoplasmic vacuole, nucleus (AnkA target; GO:0005634), mitochondria (Ats-1 target; GO:0005739), autophagosome (GO:0005776).

8. Temporal Development. Onset acute, ~5–14 days post-tick bite; disease is typically self-limited and resolves rapidly with doxycycline (fever ≤1 day). Untreated disease can progress to complications; chronic human infection is not established (unlike persistent reservoir-host infection).

9. Inheritance and Population. No inheritance (infectious). Epidemiology: rising US incidence; concentrated in Northeast/Upper Midwest; seasonal July peak; slight male predominance (53.9%); older adults over-represented among hospitalized. Not a genetic disease — penetrance/expressivity/founder effects N/A.

10. Diagnostics. Whole-blood PCR (primary, sensitive early), IFA serology (paired acute/convalescent; insensitive early), Giemsa blood smear morulae (specific but ~5.6% sensitive early). Supportive labs: CBC (thrombocytopenia, leukopenia), elevated transaminases, elevated CRP. Differential: ehrlichiosis, Lyme disease, babesiosis, other acute febrile illnesses.

11. Outcome/Prognosis. Good: lethality ~3.0%, sequelae ~2.1%. Complications in ~40.5%. Prognostic factors: advanced age, immunosuppression, altered mental status, comorbidities. Rapid recovery with timely doxycycline.

12. Treatment. Doxycycline first-line, all ages (NCIT:C731); rifampin in pregnancy/intolerance (NCIT:C692). Severe/HLH cases: doxycycline + corticosteroids ± anakinra (IL-1RA). No gene/cell/RNA therapies applicable.

13. Prevention. No vaccine. Primary prevention = tick-bite avoidance (permethrin-treated clothing, DEET/IR3535 repellents, tick checks, landscape/rodent-targeted interventions). Secondary prevention = early empiric treatment. Public health: vector/reservoir control, health education.

14. Other Species / Natural Disease. Natural disease in horses (equine granulocytic anaplasmosis), dogs, cats, and ruminants (tick-borne fever with abortion, reduced milk yield, immunosuppression). Shared strains across humans/dogs/horses/cats confirm zoonotic cross-species susceptibility.

15. Model Organisms. Mouse models (used to establish IFN-γ/STAT1 immunopathology); naturally infected horses, sheep/lambs (msp2/p44 persistence studies), and reservoir woodrats/Peromyscus (antigenic variation). In vitro: HL-60 promyelocytic cells, human PMNs, HEK293T (effector studies). These recapitulate neutrophil infection, cytopenias, and immunopathology; they do not fully capture human clinical heterogeneity.

Limitations and Knowledge Gaps

Immunopathology in humans is inferred, not directly demonstrated. The IFN-γ/STAT1 model is strongest in mouse and horse systems; direct human tissue-level causal evidence is limited, resting on the burden–severity dissociation and cytokine-mediated CSF findings.
Host genetic determinants of human severity are unknown. Why some patients (beyond age/immunosuppression) develop severe disease or HLH is not defined; no human susceptibility loci have been mapped.
Mechanistic link from subversion to specific cytopenias is incomplete. The pathways producing thrombocytopenia and leukopenia (marrow suppression vs peripheral consumption/sequestration) are not fully resolved.
Effector biology gaps. Only 3 of ≥6 T4SS effectors are functionally characterized; the full effector repertoire and its integration with host signaling remain open.
Diagnostic performance data are heterogeneous. Sensitivity/specificity of PCR vs serology across disease stages come from varied, sometimes small cohorts.
No controlled trial data exist for HLH-directed immunomodulation in anaplasmosis; evidence is anecdotal (case reports).
Publication/case-report bias likely inflates the apparent frequency of rare severe manifestations (CNS, HLH, thromboembolism) relative to the true population.

Proposed Follow-up Experiments / Actions

Human immunophenotyping study: longitudinal serum cytokine profiling (IFN-γ, IL-1, IL-6, IL-18, ferritin) and pSTAT1 in circulating leukocytes in HGA patients stratified by severity, to directly test the immunopathology model and identify HLH-risk biomarkers.
Host-genetics of severity: targeted or exome sequencing of severe/HLH HGA cases (e.g., PRF1, UNC13D, STXBP2 HLH genes) to test whether occult HLH predisposition underlies severe outcomes.
Effector–pathway mapping: complete the functional characterization of the remaining T4SS effectors and their host targets using proximity labeling/interactomics in primary human neutrophils.
Mechanistic dissection of cytopenias: bone marrow and platelet-kinetic studies (or murine models) to determine whether thrombocytopenia/leukopenia are marrow-suppressive or consumptive.
Diagnostics benchmarking: prospective multicenter head-to-head evaluation of PCR vs IFA vs smear vs emerging antigen/metagenomic assays across defined time-since-onset windows.
Immunomodulation registry: structured case registry (or adaptive platform) for anaplasmosis-associated HLH to evaluate doxycycline ± corticosteroids ± anakinra outcomes.
Prevention translation: field evaluation of rodent-targeted acaricide/vaccine interventions specifically on Ap-ha (human-active) variant prevalence, not just total A. phagocytophilum.

Consensus Answer

Human granulocytic anaplasmosis (HGA; MONDO:0005118) is an acute, usually self-limiting tick-borne febrile illness caused by the obligate intracellular bacterium Anaplasma phagocytophilum (human-active "Ap-ha" variant), transmitted mainly by Ixodes ticks and characterized by fever with thrombocytopenia, transaminitis, and leukopenia. The pathogen uniquely infects neutrophils — entering via PSGL-1/sialyl-Lewis^x and surviving via Type IV secretion effectors AnkA (HDAC1-mediated epigenetic silencing of the NADPH-oxidase gene CYBB) and Ats-1 (mitochondrial anti-apoptosis and autophagy hijacking) — while tissue injury is driven by an IFN-γ/STAT1 immunopathologic host response rather than direct bacterial damage. HGA has no human genetic etiology or vaccine; diagnosis is by whole-blood PCR and IFA serology, doxycycline is rapidly curative first-line therapy (rifampin in pregnancy), and prognosis is good (lethality ~3%), with advanced age and immunosuppression predicting severe disease.

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These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0016575 (obsolete histone deacetylation) (1 mention)

33 of 34 terms resolved to a current term; the rest could not be looked up either way.

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Classifications

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Diagnosis

Prevalence

Infectious Agent

Transmission

Source YAML

References & Deep Research

Deep Research

Human Granulocytic Anaplasmosis (HGA): Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1: HGA is a tick-borne infection of neutrophils presenting as a febrile illness with cytopenias

Finding 2: A. phagocytophilum survives in neutrophils by subverting bactericidal functions and delaying apoptosis

Finding 3: Type IV secretion effectors AnkA and Ats-1 drive intracellular subversion

Finding 4: Doxycycline is highly effective; advanced age and immunosuppression predict severe disease

Finding 5: Entry via PSGL-1/sialyl-Lewis^x and persistence via msp2(p44) antigenic variation

Finding 6: HGA is an emerging Ixodes-borne zoonosis; only the Ap-ha variant is human-pathogenic

Finding 7: HGA tissue injury is immunopathologic, driven by IFN-γ/STAT1 signaling

Finding 8: Diagnosis relies on PCR and serology; blood-smear morulae have low early sensitivity

Finding 9: Doxycycline is first-line for all ages; rifampin is the alternative in pregnancy

Finding 10: A. phagocytophilum is a multi-host zoonotic pathogen (granulocytic anaplasmosis / tick-borne fever)

Finding 11: Severe anaplasmosis can trigger secondary HLH, a treatable immune-dysregulation complication

Finding 12: Integrated model — pathogen-driven neutrophil subversion produces host IFN-γ/STAT1 immunopathology, reversible with doxycycline

Mechanistic Model / Interpretation

Ordered causal chain (initiating exposure → clinical manifestation)

Schematic

Upstream vs downstream

Evidence Base

Section-by-Section Knowledge Base Content

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Consensus Answer

Artifacts

Reference Validation

Term Validation

Obsolete terms