Ebola Virus Disease (EVD)

MONDO:0005737 Pathograph 12

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5
Pathophys.
18
Phenotypes
12
Pathograph
6
Genes
3
Treatments
5
Subtypes
2
Deep Research
◆

Subtypes

5
Zaire Ebolavirus
The most common and deadliest strain, responsible for the majority of Ebola outbreaks.
Show evidence (3 references)
PMID:8800808 PARTIAL
"The reemergence of Ebola, subtype Zaire, in Kikwit 1995 caused a worldwide sensation, since it struck after a sensibilization on the danger of Ebola virus disease."
Supports Zaire subtype outbreak relevance, but only partially supports prevalence/deadliness ranking.
PMID:23327370 PARTIAL
"The re-emergence of EHF outbreaks in Gabon and Republic of the Congo were concomitant with an increase in mortality amongst gorillas and chimpanzees infected with ZEBOV."
Supports ZEBOV outbreak association in listed geographies, but only partially supports the broader subtype claim.
PMID:24795448 PARTIAL
"The causative agent has now been identified as an outlier strain of Zaire Ebola virus."
Supports Zaire strain identification in an outbreak, but only partially supports prevalence/deadliness framing.
Sudan Ebolavirus
Second most prevalent strain, associated with large outbreaks in Africa.
Show evidence (5 references)
PMID:37750724 PARTIAL
"Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized."
Supports Sudan virus outbreak in Uganda, but only partially supports the broader prevalence ranking.
PMID:28643203 PARTIAL
"Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus"
Supports subtype identity, but only partially supports prevalence/outbreak-size claims.
PMID:31806422 PARTIAL
"The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus."
Supports subtype identity only, not prevalence ranking.
+ 2 more references
Bundibugyo Ebolavirus
Identified in Uganda, this strain has caused smaller outbreaks.
Show evidence (2 references)
PMID:21122234 SUPPORT
"The first known Ebola hemorrhagic fever (EHF) outbreak caused by Bundibugyo Ebola virus occurred in Bundibugyo District, Uganda, in 2007. Fifty-six cases of EHF were laboratory confirmed."
This reference supports the statement by confirming the occurrence of a Bundibugyo Ebola virus outbreak in Uganda.
PMID:34467242 SUPPORT
"Bundibugyo virus (BDBV) is one of four ebolaviruses known to cause disease in humans. Bundibugyo virus disease (BVD) outbreaks occurred in 2007-2008 in Bundibugyo District, Uganda, and in 2012 in Isiro, Province Orientale, Democratic Republic of the Congo."
This reference also supports the statement by citing outbreaks of Bundibugyo Ebola virus in Uganda.
Taï Forest Ebolavirus
Known for a single outbreak in the Ivory Coast.
Show evidence (3 references)
PMID:28643203 PARTIAL
"Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus"
Supports Taï Forest as a human-pathogenic ebolavirus, but does not directly support the single-outbreak Ivory Coast claim.
PMID:31806422 PARTIAL
"The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, and Ebola virus (previously known as Zaire ebolavirus)"
Supports species identity only; does not directly support outbreak count/location claim.
PMID:37750724 NO_EVIDENCE
"Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized, and the genetic relatedness of the new variant is evaluated."
This reference discusses the Sudan virus disease outbreak in Uganda in 2022 and does not mention the Tai Forest ebolavirus or outbreaks in Ivory Coast.
Reston Ebolavirus
Only strain identified outside Africa; found in the Philippines and has not caused disease in humans.
Show evidence (2 references)
PMID:21987747 PARTIAL
"Reston ebolavirus infection event in domestic pigs has triggered continuing epidemiologic investigations among Philippine health and veterinary agencies... The first one in 1989 was the first-ever Ebola virus that emerged outside of Africa and was also the first known natural infection of Ebola..."
The reference supports that Reston ebolavirus was identified outside of Africa in the Philippines and that it had not caused disease in humans, but it does not affirmatively state that it is the only strain identified outside of Africa.
PMID:28643203 SUPPORT
"To date, no documented cases of human disease have been associated with Reston virus."
This reference supports the claim that Reston ebolavirus has not caused disease in humans.
⚙

Pathophysiology

5
Viral Entry via Endocytosis
Ebola virus enters host cells through receptor-mediated macropinocytosis. The virus attaches to phosphatidylserine receptors like TIM-1 (HAVCR1) and is internalized into endosomes. Cathepsins B and L cleave the viral glycoprotein (GP), followed by binding to the essential receptor NPC1 in late endosomes/lysosomes, triggering membrane fusion and release of viral genome into the cytoplasm.
monocyte link macrophage link dendritic cell link
symbiont entry into host cell link
Immune Evasion and Viral Replication
Ebola viral proteins VP35 and VP24 antagonize the host interferon response. VP35 binds dsRNA and blocks RIG-I signaling, while VP24 prevents STAT1 nuclear import, thereby suppressing type I interferon signaling. This allows rapid viral replication and high viremia in infected monocytes, macrophages, and dendritic cells.
monocyte link macrophage link dendritic cell link
Endothelial Dysfunction and Vascular Leak
Ebola virus glycoprotein (GP) and secreted GP (sGP) contribute to endothelial cell activation and barrier disruption. This leads to increased vascular permeability, fluid extravasation, and hypovolemic shock. Endothelial dysfunction is a central feature of Ebola hemorrhagic fever.
endothelial cell link
blood vessel link
Coagulopathy and Disseminated Intravascular Coagulation
Ebola infection triggers systemic inflammatory response with cytokine release, endothelial activation, and tissue factor pathway activation. This leads to thromboinflammation, platelet activation, consumptive coagulopathy, and disseminated intravascular coagulation (DIC), resulting in hemorrhagic manifestations.
blood coagulation link
blood vessel link
Multiorgan Involvement
Ebola virus infects multiple organs including liver, spleen, lymph nodes, and kidneys. Hepatic dysfunction with elevated liver enzymes (AST > ALT pattern) and splenic involvement contribute to multiorgan failure in severe cases.
liver link spleen link
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Vascular Dysfunction and Death' (from 'Hemorrhage') not found in named elements
Pathograph: causal mechanism network for Ebola Virus Disease (EVD) Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

18
Blood 3
Hemorrhage VERY_FREQUENT Abnormal bleeding (HP:0001892)
Sequelae: Hypovolemic Shock Multiorgan Failure Vascular Dysfunction and Death
Show evidence (4 references)
PMID:32487785 SUPPORT
"It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors."
The literature confirms that hemorrhagic symptoms are a key diagnostic feature of EVD.
PMID:28484180 SUPPORT
"Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and nonhuman primates, with human case fatality rates of up to 90%."
The literature confirms severe hemorrhagic fever as a phenotype of EVD.
PMID:30893774 NO_EVIDENCE
"Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family."
Snippet supports severity/fatality but does not directly provide hemorrhage-specific evidence.
+ 1 more reference
Thrombocytopenia FREQUENT Thrombocytopenia (HP:0001873)
Sequelae: Increased Risk of Bleeding
Show evidence (3 references)
PMID:32487785 PARTIAL
"Transmission of EBoV has been reported in various ways, including human to human transmission through close contact with blood and bodily fluids... It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least..."
The literature mentions hemorrhagic symptoms but does not specifically mention thrombocytopenia or its frequency.
PMID:25679971 PARTIAL
"Understanding bleeding in Ebola virus disease."
The reference discusses bleeding in Ebola virus disease but does not specifically mention thrombocytopenia or its frequency.
PMID:35446128 PARTIAL
"Ebola virus (EBV) disease (EVD) is a highly virulent systemic disease characterized by an aggressive systemic inflammatory response and impaired vascular and coagulation systems, often leading to uncontrolled hemorrhaging and death."
The literature discusses impaired vascular and coagulation systems, which can be related to thrombocytopenia, but does not specifically mention its frequency.
Increased Risk of Bleeding FREQUENT Abnormal bleeding (HP:0001892)
Cardiovascular 1
Hypovolemic Shock FREQUENT Shock (HP:0031273)
Digestive 4
Vomiting VERY_FREQUENT Vomiting (HP:0002013)
Show evidence (3 references)
PMID:25972150 PARTIAL
"Common gastrointestinal manifestations include...nausea and vomiting-60%...The diarrhea and nausea and vomiting frequently produce profound, life-threatening hypovolemia."
While vomiting is a common manifestation and can lead to severe consequences like life-threatening hypovolemia, the literature does not specifically categorize vomiting itself as "severe." The severity is associated with the complications resulting from vomiting and other symptoms.
PMID:32080199 PARTIAL
"EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs..."
This reference indicates the inclusion of gastrointestinal signs in EVD, which can imply vomiting, but does not specifically mention the frequency or severity of vomiting.
PMID:27717513 PARTIAL
"The clinical spectrum of Ebola virus disease (EVD) ranges from very serious forms with organ failure and death within days to paucisymptomatic forms and perhaps even asymptomatic."
This suggests variability in EVD presentation, acknowledging severe forms, but it does not specify the severity or frequency of vomiting in particular.
Diarrhea VERY_FREQUENT Diarrhea (HP:0002014)
Sequelae: Dehydration Electrolyte Imbalances
Show evidence (3 references)
PMID:32080199 PARTIAL
"EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome."
Supports gastrointestinal involvement broadly, but only partially supports diarrhea-specific severity/frequency.
PMID:25972150 SUPPORT
"Common gastrointestinal manifestations include diarrhea-70 %."
This directly supports the statement by noting that diarrhea is a common (70% frequency) gastrointestinal manifestation.
PMID:34986351 SUPPORT
"During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome."
The reference highlights that severe gastrointestinal symptoms, including diarrhea, were common and associated with poor outcomes.
Hepatitis FREQUENT Hepatitis (HP:0012115)
Sequelae: Elevated Liver Enzymes Impaired Liver Function
Show evidence (4 references)
PMID:2822180 PARTIAL
"Even though HAV, HBV and HNANB viruses are responsible for most of the viral hepatitis cases, many other viruses have been reported to cause hepatic injury. These viruses may involve the liver, either as part of a systemic illness (e.g. EBV, CMV, HSV) or as the primary target organ (e.g. yellow..."
The reference indicates that Ebola virus can cause hepatic injury, but clinically overt hepatocellular dysfunction is rare. This partially supports the statement as it acknowledges hepatic involvement but suggests that severe liver dysfunction is not frequent.
PMID:25972150 PARTIAL
"The mean serum AST and ALT levels are each about 200/UL, with an unusual pattern for viral hepatitis of AST > ALT."
The reference indicates elevated liver enzymes (AST and ALT) in Ebola virus infection, which supports the part of the statement regarding elevated liver enzymes. However, it does not confirm frequent impaired liver function or hepatitis as a common sequela.
PMID:37170900 PARTIAL
"Results illustrate that EBOV causes macrophage phenotype alterations as well as neutrophil influx and prominent activation of interferon host responses in the liver."
The reference provides evidence of liver involvement and immune response alterations in Ebola virus infection, which can be associated with hepatic dysfunction. However, it does not explicitly state that hepatitis or impaired liver function is frequent.
+ 1 more reference
Impaired Liver Function FREQUENT Decreased liver function (HP:0001410)
Metabolism 4
Fever VERY_FREQUENT Fever (HP:0001945)
Show evidence (2 references)
PMID:32080199 SUPPORT
"EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome."
The literature indicates that fever is a very frequent symptom of Ebola Virus Disease (EVD).
PMID:28457350 NO_EVIDENCE
"This review highlights the range of aspects of EVD that the authors find are relevant to laboratory medicine, including the need for robust prediagnostic and laboratory processing algorithms to inform sampling of suspect patients, the vast majority of whom, in resource-rich settings, will have..."
Snippet addresses laboratory workflow context and does not directly provide fever-frequency evidence.
Dehydration FREQUENT Dehydration (HP:0001944)
Electrolyte Imbalances FREQUENT Abnormal blood ion concentration (HP:0003111)
Elevated Liver Enzymes FREQUENT Elevated circulating hepatic transaminase concentration (HP:0002910)
Nervous System 1
Headache OCCASIONAL Headache (HP:0002315)
Show evidence (3 references)
PMID:31874716 SUPPORT
"The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%)..."
This study lists headache as one of the main clinical signs in children with EVD, supporting the statement that headache is an occasional neurologic symptom of EVD.
PMID:33493959 NO_EVIDENCE
"In patients with EVD, neurologic manifestations range from mild symptoms such as confusion to severe neurologic diseases such as meningitis and encephalitis. Altered mental status, from mild confusion to delirium with hallucinations, may also occur."
Snippet does not directly mention headache.
PMID:26983037 SUPPORT
"Survivors reported musculoskeletal pain (70%), headache (48%), and ocular problems (14%)."
This study reports that 48% of EVD survivors experienced headaches, supporting the statement that headache is an occasional neurologic symptom of EVD.
Constitutional 3
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:38840082 PARTIAL
"The pooled prevalence was... fatigue 25% (95% CI: 19%-31%)"
Fatigue is reported as a symptom in 25% of EVD survivors, which indicates it is relatively common but not 'very frequent' as the statement suggests.
Myalgia FREQUENT Myalgia (HP:0003326)
Show evidence (1 reference)
PMID:38840082 SUPPORT
"The pooled prevalence was: arthralgia 50% (95% CI: 41%-59%); headache 44% (95% CI: 36%-52%); myalgia 32% (95% CI: 26%-38%)"
The meta-analysis shows that myalgia has a pooled prevalence of 32% among Ebola Virus Disease (EVD) survivors, indicating it is a frequent musculoskeletal symptom.
Abdominal Pain FREQUENT Abdominal pain (HP:0002027)
Show evidence (2 references)
PMID:25972150 SUPPORT
"Common gastrointestinal manifestations include diarrhea-70 %, nausea and vomiting-60 %, and abdominal pain-45 %."
The literature indicates that abdominal pain occurs in 45% of EVD cases, supporting the claim that it is a frequent gastrointestinal manifestation.
PMID:31874716 SUPPORT
"The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%), vomiting (41.8%), abdominal pain (29.5%), and diarrhea (28.8%)."
The study shows that abdominal pain was observed in 29.5% of children with EVD, supporting the statement that it is a frequent gastrointestinal symptom.
Other 2
Maculopapular Rash FREQUENT
Show evidence (1 reference)
PMID:25780982 SUPPORT
"The main cutaneous finding of Ebola is a nonspecific maculopapular rash that appears between day four and six of disease."
The statement is supported as the primary dermatologic phenotype associated with Ebola Virus Disease (EVD) is a nonspecific maculopapular rash, and it is noted as a main cutaneous finding.
Multiorgan Failure FREQUENT
HPO does not have a specific term for multiple organ dysfunction syndrome
🧬

Genetic Associations

6
NPC1 (Host factor)
HAVCR1 (Host factor)
SLC39A9 (Host factor)
PIK3C3 (Host factor)
CTSB (Host factor)
CTSL (Host factor)
💊

Treatments

3
Supportive Care
Action: supportive care MAXO:0000950
Includes rehydration, symptomatic treatment to manage fever, bleeding, and pain.
Show evidence (3 references)
PMID:37355146 SUPPORT
"Early detection and supportive care can enhance the likelihood of survival. This includes intravenous fluids, electrolyte replacement, and treatment of secondary infections."
The provided literature supports that supportive care, including rehydration and symptomatic treatment, is a key component in the treatment of Ebola Virus Disease (EVD).
PMID:28646340 SUPPORT
"Clinical management of EVD combines supportive and symptomatic care while also addressing the patient's emotional and mental health needs."
This literature indicates the combination of supportive and symptomatic care is part of the clinical management of EVD.
PMID:29054555 SUPPORT
"Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief."
The evidence-based guidelines for supportive care of patients with EVD include recommendations that align with rehydration and symptomatic treatments for managing fever, bleeding, and pain.
Experimental Therapies
Action: antiviral agent therapy MAXO:0000168
Includes antiviral drugs, immune therapies, and blood products from survivors containing antibodies.
Show evidence (5 references)
PMID:27337455 SUPPORT
"The armamentarium against EVD eventually included biologics such as monoclonal antibodies, convalescent plasma, and vaccines as well as small molecule therapeutics such as small interfering RNAs and nucleoside analogs."
The reference mentions the use of various experimental therapies including immune therapies (monoclonal antibodies), blood products (convalescent plasma), and small molecule therapeutics (antiviral drugs).
PMID:11766882 PARTIAL
"This review describes Ebola viruses, with a particular focus on the status of research efforts to develop vaccines and therapeutics and to identify the immune mechanisms of protection."
Supports historical therapeutic research context, but only partially supports specific experimental therapy modalities.
PMID:25457751 SUPPORT
"Recently, the use of convalescent blood products was proposed by the WHO as one early option for treating patients with Ebola virus disease."
The reference confirms the use of convalescent blood products as a treatment strategy for EVD, supporting the statement.
+ 2 more references
Vaccination
Action: vaccination MAXO:0001017
The rVSV-ZEBOV vaccine has been shown to be effective in preventing Ebola infection.
Show evidence (4 references)
PMID:28017403 SUPPORT
"The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters."
The study shows that rVSV-ZEBOV vaccine offers substantial protection against Ebola virus disease, supporting the statement that it is effective in preventing Ebola infection.
PMID:32243796 SUPPORT
"Ervebo is the first licensed vaccine for prevention of Ebola virus disease."
The article states that Ervebo (rVSV-ZEBOV) is licensed for the prevention of Ebola virus disease, supporting the statement that the vaccine is effective in preventing Ebola infection.
PMID:33873076 SUPPORT
"Currently, two vaccines: Ervebo (rVSV-ZEBOV) and a two-dose combination of Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) have been licensed and in use."
The abstract mentions that Ervebo (rVSV-ZEBOV) has been licensed and is being used to prevent Ebola Virus Disease, supporting the statement that it is effective in preventing infection.
+ 1 more reference
🌍

Environmental Factors

1
Animal Reservoirs
Animal reservoir exposure link
Fruit bats are considered the natural hosts; transmission also occurs through handling of infected wild animals.
Show evidence (4 references)
PMID:17848072 SUPPORT
"Among the various animals captured and analyzed, three species of fruit bats (suborder Megachiroptera) were found asymptomatically and naturally infected with Ebola virus: Hypsignathus monstrosus (hammer-headed fruit beats), Epomops franqueti (singing fruit bats), and Myonycteris torquata..."
This study confirms that certain species of fruit bats serve as Ebola virus reservoirs, supporting the notion that fruit bats are natural hosts of the virus.
PMID:28573636 PARTIAL
"Although an ebolavirus natural reservoir has yet to be identified, the majority of disease ecologists believe the reservoir to belong to the order Chiroptera (bats)."
While bats are strongly suspected to be the natural reservoir, the virus has not been isolated definitively from them, providing partial but not conclusive support.
PMID:26757869 SUPPORT
"Fruits bats are its natural reservoir, the transmission to humans is across wild animals (especially primates) and the propagation in human populations is through bodily fluid contact"
This literature indicates that fruit bats are considered the natural reservoir for Ebola, supporting the statement.
+ 1 more reference
🔬

Biochemical Markers

2
Ebola Virus Antigen (Positive)
Show evidence (2 references)
PMID:26874083 PARTIAL
"The diagnosis of Ebola virus disease relies on the detection of viral RNA in blood by real-time reverse-transcription PCR."
Supports RT-PCR RNA detection, but only partially supports antigen-specific assay claim.
PMID:28887479 SUPPORT
"We have developed a reduced graphene oxide-based field-effect transistor method for real-time detection of the Ebola virus antigen."
This reference provides additional support for antigen detection methods, which indirectly supports the overall assertion.
Ebola Virus RNA (Positive)
Show evidence (2 references)
PMID:26874083 SUPPORT
"The diagnosis of Ebola virus disease relies on the detection of viral RNA in blood by real-time reverse-transcription PCR."
This reference directly supports the statement that RT-PCR assays are used to detect the presence of Ebola Virus RNA.
PMID:26465681 SUPPORT
"BACKGROUND: Ebola virus has been detected in the semen of men after their recovery from Ebola virus disease (EVD)... Semen specimens obtained at baseline were tested by means of a quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay..."
This reference also supports the usage of RT-PCR assays for detecting Ebola Virus RNA in biological samples.
{ }

Source YAML

click to show 
name: Ebola Virus Disease (EVD)
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-16T20:19:38Z'
categories:
- Viral Hemorrhagic Fever
- Zoonotic Infectious Disease
has_subtypes:
- name: Zaire Ebolavirus
  description: The most common and deadliest strain, responsible for the majority of Ebola outbreaks.
  geography:
  - Democratic Republic of Congo
  - Gabon
  evidence:
  - reference: PMID:8800808
    reference_title: "Emerging and reemerging of filoviruses."
    supports: PARTIAL
    snippet: The reemergence of Ebola, subtype Zaire, in Kikwit 1995 caused a worldwide sensation, since it struck after a sensibilization on the danger of Ebola virus disease.
    explanation: Supports Zaire subtype outbreak relevance, but only partially supports prevalence/deadliness ranking.
  - reference: PMID:23327370
    reference_title: "Ebola virus outbreaks in Africa: past and present."
    supports: PARTIAL
    snippet: The re-emergence of EHF outbreaks in Gabon and Republic of the Congo were concomitant with an increase in mortality amongst gorillas and chimpanzees infected with ZEBOV.
    explanation: Supports ZEBOV outbreak association in listed geographies, but only partially supports the broader subtype claim.
  - reference: PMID:24795448
    reference_title: "The 2014 Ebola virus disease outbreak in West Africa."
    supports: PARTIAL
    snippet: The causative agent has now been identified as an outlier strain of Zaire Ebola virus.
    explanation: Supports Zaire strain identification in an outbreak, but only partially supports prevalence/deadliness framing.
- name: Sudan Ebolavirus
  description: Second most prevalent strain, associated with large outbreaks in Africa.
  geography:
  - Sudan
  - Uganda
  evidence:
  - reference: PMID:37750724
    reference_title: "Molecular characterization of the 2022 Sudan virus disease outbreak in Uganda."
    supports: PARTIAL
    snippet: Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized.
    explanation: Supports Sudan virus outbreak in Uganda, but only partially supports the broader prevalence ranking.
  - reference: PMID:28643203
    reference_title: "Nonhuman Primate Models of Ebola Virus Disease."
    supports: PARTIAL
    snippet: 'Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus'
    explanation: Supports subtype identity, but only partially supports prevalence/outbreak-size claims.
  - reference: PMID:31806422
    reference_title: "Ebola virus disease: An emerging and re-emerging viral threat."
    supports: PARTIAL
    snippet: The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus.
    explanation: Supports subtype identity only, not prevalence ranking.
  - reference: PMID:37355146
    reference_title: "Ebola virus disease: A narrative review."
    supports: PARTIAL
    snippet: In 1976, the disease emerged in two simultaneous outbreaks in Sudan and the Democratic Republic of Congo.
    explanation: Supports historical Sudan-associated emergence context, but only partially supports the full subtype descriptor.
  - reference: PMID:34420499
    reference_title: "Perceptions of ebola virus disease among the bambuti hunter group: a mixed-methods study."
    supports: NO_EVIDENCE
    snippet: The second largest Ebola virus disease (EVD) epidemic occurred in the Democratic Republic of the Congo (DRC) from 2018-20.
    explanation: This snippet describes a DRC epidemic without direct Sudan ebolavirus evidence.
- name: Bundibugyo Ebolavirus
  description: Identified in Uganda, this strain has caused smaller outbreaks.
  geography:
  - Uganda
  evidence:
  - reference: PMID:21122234
    reference_title: "Proportion of deaths and clinical features in Bundibugyo Ebola virus infection, Uganda."
    supports: SUPPORT
    snippet: The first known Ebola hemorrhagic fever (EHF) outbreak caused by Bundibugyo Ebola virus occurred in Bundibugyo District, Uganda, in 2007. Fifty-six cases of EHF were laboratory confirmed.
    explanation: This reference supports the statement by confirming the occurrence of a Bundibugyo Ebola virus outbreak in Uganda.
  - reference: PMID:34467242
    reference_title: "Molecular analysis of the 2012 Bundibugyo virus disease outbreak."
    supports: SUPPORT
    snippet: Bundibugyo virus (BDBV) is one of four ebolaviruses known to cause disease in humans. Bundibugyo virus disease (BVD) outbreaks occurred in 2007-2008 in Bundibugyo District, Uganda, and in 2012 in Isiro, Province Orientale, Democratic Republic of the Congo.
    explanation: This reference also supports the statement by citing outbreaks of Bundibugyo Ebola virus in Uganda.
- name: Taï Forest Ebolavirus
  description: Known for a single outbreak in the Ivory Coast.
  geography:
  - Ivory Coast
  evidence:
  - reference: PMID:28643203
    reference_title: "Nonhuman Primate Models of Ebola Virus Disease."
    supports: PARTIAL
    snippet: 'Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus'
    explanation: Supports Taï Forest as a human-pathogenic ebolavirus, but does not directly support the single-outbreak Ivory Coast claim.
  - reference: PMID:31806422
    reference_title: "Ebola virus disease: An emerging and re-emerging viral threat."
    supports: PARTIAL
    snippet: The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, and Ebola virus (previously known as Zaire ebolavirus)
    explanation: Supports species identity only; does not directly support outbreak count/location claim.
  - reference: PMID:37750724
    reference_title: "Molecular characterization of the 2022 Sudan virus disease outbreak in Uganda."
    supports: NO_EVIDENCE
    snippet: Here, the 2022 Sudan virus disease (SVD) outbreak in Mubende District, Uganda, is summarized, and the genetic relatedness of the new variant is evaluated.
    explanation: This reference discusses the Sudan virus disease outbreak in Uganda in 2022 and does not mention the Tai Forest ebolavirus or outbreaks in Ivory Coast.
- name: Reston Ebolavirus
  description: Only strain identified outside Africa; found in the Philippines and has not caused disease in humans.
  geography:
  - Philippines
  evidence:
  - reference: PMID:21987747
    reference_title: "Reston ebolavirus in humans and animals in the Philippines: a review."
    supports: PARTIAL
    snippet: Reston ebolavirus infection event in domestic pigs has triggered continuing epidemiologic investigations among Philippine health and veterinary agencies... The first one in 1989 was the first-ever Ebola virus that emerged outside of Africa and was also the first known natural infection of Ebola virus in nonhuman primates.
    explanation: The reference supports that Reston ebolavirus was identified outside of Africa in the Philippines and that it had not caused disease in humans, but it does not affirmatively state that it is the only strain identified outside of Africa.
  - reference: PMID:28643203
    reference_title: "Nonhuman Primate Models of Ebola Virus Disease."
    supports: SUPPORT
    snippet: To date, no documented cases of human disease have been associated with Reston virus.
    explanation: This reference supports the claim that Reston ebolavirus has not caused disease in humans.
prevalence:
- population: Central and West Africa
  percentage: Outbreak-dependent
  evidence:
  - reference: PMID:31002071
    reference_title: "Serologic Prevalence of Ebola Virus in Equatorial Africa."
    supports: SUPPORT
    snippet: Our results suggest a serologic prevalence of 2%-3.5% in the Republic of the Congo and the Democratic Republic of the Congo, which have reported outbreaks of infection with EBOV. In addition we detected a seroprevalence of 1.3% in southern Cameroon, which indicated a low risk for exposure in this region.
    explanation: The study shows variation in serologic prevalence of EBOV in different regions of Central Africa, which supports the statement that EVD prevalence is outbreak-dependent and varies by region in Central Africa.
  - reference: PMID:34077889
    reference_title: "Impact of recurrent outbreaks of Ebola virus disease in Africa: a meta-analysis of case fatality rates."
    supports: SUPPORT
    snippet: 'The most EVD-affected countries were the Democratic Republic of Congo with five outbreaks and a pooled CFR of 65% (95% CI: 59-71%), followed by Uganda with three outbreaks and CFR of 83% (95% CI: 60-99%).'
    explanation: This meta-analysis shows varying case fatality rates and the prevalence of EVD outbreaks in Central Africa, supporting the statement that the prevalence is outbreak-dependent.
progression:
- phase: Onset
  incubation_days: 2-21
  evidence:
  - reference: PMID:25763588
    reference_title: "[Ebola virus disease]."
    supports: SUPPORT
    snippet: The incubation period of the disease ranges from 2 to 21 days.
    explanation: The literature specifies that the incubation period for Ebola virus disease ranges from 2 to 21 days, which aligns with the statement provided.
infectious_agent:
- name: Ebola Virus
  infectious_agent_term:
    preferred_term: Ebola virus
    term:
      id: NCBITaxon:1570291
      label: Ebola virus
  evidence:
  - reference: PMID:32080199
    reference_title: "Ebola virus disease."
    supports: SUPPORT
    snippet: Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV).
    explanation: The literature clearly states that EVD is caused by the Ebola virus.
  - reference: PMID:28643203
    reference_title: "Nonhuman Primate Models of Ebola Virus Disease."
    supports: SUPPORT
    snippet: 'Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Taï Forest virus'
    explanation: This reference confirms that Ebola virus (EBOV) is indeed an infectious agent of EVD.
  - reference: PMID:24040779
    reference_title: "Evolutionary history of Ebola virus."
    supports: SUPPORT
    snippet: Since Ebola virus was discovered in 1970s, the virus has persisted in Africa and sporadic fatal outbreaks in humans and non-human primates have been reported.
    explanation: This reference states that Ebola virus is responsible for outbreaks in humans, indicating it as the infectious agent for Ebola virus disease.
  - reference: PMID:33734027
    reference_title: "Pathogenicity and Virulence of Ebolaviruses with Species- and Variant-specificity."
    supports: SUPPORT
    snippet: Ebola virus (EBOV), belonging to the species Zaire ebolavirus in the genus Ebolavirus, causes a severe febrile illness in humans with case fatality rates (CFRs) up to 90%.
    explanation: This literature directly links Ebola virus (EBOV) to the severe illness known as Ebola Virus Disease (EVD).
transmission:
- name: Direct Fluid Transmission
  description: Virus is transmitted through direct contact with the blood, secretions, organs, or other bodily fluids of infected individuals or animals.
  evidence: []
- name: Contaminated Surfaces
  description: The virus can survive on surfaces, infecting individuals through contact with these contaminated surfaces.
  evidence:
  - reference: PMID:25698835
    reference_title: "Transmission of Ebola viruses: what we know and what we do not know."
    supports: PARTIAL
    snippet: Available evidence demonstrates that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, but this is based on a limited number of studies. Key areas requiring further study include... (ii) the role of environmental contamination and fomite transmission...
    explanation: While the reference acknowledges the role of environmental contamination and fomite transmission, it indicates that this is an area that requires further study and is not yet conclusively established as a primary mode of transmission.
phenotypes:
- category: Systemic
  name: Fever
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:32080199
    reference_title: "Ebola virus disease."
    supports: SUPPORT
    snippet: EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome.
    explanation: The literature indicates that fever is a very frequent symptom of Ebola Virus Disease (EVD).
  - reference: PMID:28457350
    reference_title: "Ebola Virus Disease: An Update on Epidemiology, Symptoms, Laboratory Findings, Diagnostic Issues, and Infection Prevention and Control Issues for Laboratory Professionals."
    supports: NO_EVIDENCE
    snippet: This review highlights the range of aspects of EVD that the authors find are relevant to laboratory medicine, including the need for robust prediagnostic and laboratory processing algorithms to inform sampling of suspect patients, the vast majority of whom, in resource-rich settings, will have another diagnosis.
    explanation: Snippet addresses laboratory workflow context and does not directly provide fever-frequency evidence.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
- category: Systemic
  name: Hemorrhage
  severity: Severe
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:32487785
    reference_title: "Clinical aspects of Ebola virus disease: a review."
    supports: SUPPORT
    snippet: It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors.
    explanation: The literature confirms that hemorrhagic symptoms are a key diagnostic feature of EVD.
  - reference: PMID:28484180
    reference_title: "[Ebola vaccine, therapeutics, and diagnostics]."
    supports: SUPPORT
    snippet: Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and nonhuman primates, with human case fatality rates of up to 90%.
    explanation: The literature confirms severe hemorrhagic fever as a phenotype of EVD.
  - reference: PMID:30893774
    reference_title: "Ebola Virus Entry: From Molecular Characterization to Drug Discovery."
    supports: NO_EVIDENCE
    snippet: Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family.
    explanation: Snippet supports severity/fatality but does not directly provide hemorrhage-specific evidence.
  - reference: PMID:35657325
    reference_title: "Natural history of Sudan ebolavirus infection in rhesus and cynomolgus macaques."
    supports: SUPPORT
    snippet: 'A group of viruses within the genus Ebolavirus causes this severe hemorrhagic disease in humans: Ebola virus (EBOV; species Zaire ebolavirus), Sudan virus (SUDV; species Sudan ebolavirus), Bundibugyo virus, and Taï Forest virus'
    explanation: The literature supports that EVD is characterized by severe systemic symptoms, including severe hemorrhagic manifestations.
  sequelae:
  - target: Hypovolemic Shock
  - target: Multiorgan Failure
  - target: Vascular Dysfunction and Death
    description: Ebola virus causes aggressive inflammatory response and impaired coagulation systems leading to hemorrhage and often death.
    evidence:
    - reference: PMID:35446128
      reference_title: "Plasma Proteomic Analysis Distinguishes Severity Outcomes of Human Ebola Virus Disease."
      supports: SUPPORT
      snippet: Ebola virus (EBV) disease (EVD) is a highly virulent systemic disease characterized by an aggressive systemic inflammatory response and impaired vascular and coagulation systems, often leading to uncontrolled hemorrhaging and death.
      explanation: This paper establishes that Ebola virus causes systemic inflammatory response and coagulation impairment leading to hemorrhage and death.
  phenotype_term:
    preferred_term: Hemorrhage
    term:
      id: HP:0001892
      label: Abnormal bleeding
- category: Gastrointestinal
  name: Vomiting
  severity: Severe
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25972150
    reference_title: "Gastrointestinal and Hepatic Manifestations of Ebola Virus Infection."
    supports: PARTIAL
    snippet: Common gastrointestinal manifestations include...nausea and vomiting-60%...The diarrhea and nausea and vomiting frequently produce profound, life-threatening hypovolemia.
    explanation: While vomiting is a common manifestation and can lead to severe consequences like life-threatening hypovolemia, the literature does not specifically categorize vomiting itself as "severe." The severity is associated with the complications resulting from vomiting and other symptoms.
  - reference: PMID:32080199
    reference_title: "Ebola virus disease."
    supports: PARTIAL
    snippet: EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome.
    explanation: This reference indicates the inclusion of gastrointestinal signs in EVD, which can imply vomiting, but does not specifically mention the frequency or severity of vomiting.
  - reference: PMID:27717513
    reference_title: "[Ebola virus disease: Clinical presentation, prognosis and treatment]."
    supports: PARTIAL
    snippet: The clinical spectrum of Ebola virus disease (EVD) ranges from very serious forms with organ failure and death within days to paucisymptomatic forms and perhaps even asymptomatic.
    explanation: This suggests variability in EVD presentation, acknowledging severe forms, but it does not specify the severity or frequency of vomiting in particular.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
- category: Gastrointestinal
  name: Diarrhea
  severity: Severe
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32080199
    reference_title: "Ebola virus disease."
    supports: PARTIAL
    snippet: EVD has a high case-fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome.
    explanation: Supports gastrointestinal involvement broadly, but only partially supports diarrhea-specific severity/frequency.
  - reference: PMID:25972150
    reference_title: "Gastrointestinal and Hepatic Manifestations of Ebola Virus Infection."
    supports: SUPPORT
    snippet: Common gastrointestinal manifestations include diarrhea-70 %.
    explanation: This directly supports the statement by noting that diarrhea is a common (70% frequency) gastrointestinal manifestation.
  - reference: PMID:34986351
    reference_title: "Ebola virus delta peptide is an enterotoxin."
    supports: SUPPORT
    snippet: During the 2013-2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome.
    explanation: The reference highlights that severe gastrointestinal symptoms, including diarrhea, were common and associated with poor outcomes.
  sequelae:
  - target: Dehydration
  - target: Electrolyte Imbalances
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
- category: Dermatologic
  name: Maculopapular Rash
  frequency: FREQUENT
  evidence:
  - reference: PMID:25780982
    reference_title: "Cutaneous manifestations of the Ebola virus."
    supports: SUPPORT
    snippet: The main cutaneous finding of Ebola is a nonspecific maculopapular rash that appears between day four and six of disease.
    explanation: The statement is supported as the primary dermatologic phenotype associated with Ebola Virus Disease (EVD) is a nonspecific maculopapular rash, and it is noted as a main cutaneous finding.
- category: Systemic
  frequency: VERY_FREQUENT
  name: Fatigue
  evidence:
  - reference: PMID:38840082
    reference_title: "Prevalence of somatic symptoms among Ebola Virus Disease (EVD) survivors in Africa: a systematic review and meta-analysis."
    supports: PARTIAL
    snippet: 'The pooled prevalence was... fatigue 25% (95% CI: 19%-31%)'
    explanation: Fatigue is reported as a symptom in 25% of EVD survivors, which indicates it is relatively common but not 'very frequent' as the statement suggests.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Musculoskeletal
  frequency: FREQUENT
  name: Myalgia
  evidence:
  - reference: PMID:38840082
    reference_title: "Prevalence of somatic symptoms among Ebola Virus Disease (EVD) survivors in Africa: a systematic review and meta-analysis."
    supports: SUPPORT
    snippet: 'The pooled prevalence was: arthralgia 50% (95% CI: 41%-59%); headache 44% (95% CI: 36%-52%); myalgia 32% (95% CI: 26%-38%)'
    explanation: The meta-analysis shows that myalgia has a pooled prevalence of 32% among Ebola Virus Disease (EVD) survivors, indicating it is a frequent musculoskeletal symptom.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
- category: Neurologic
  frequency: OCCASIONAL
  name: Headache
  evidence:
  - reference: PMID:31874716
    reference_title: "Ebola virus disease in children in Conakry and Coyah Ebola treatment centers and risk factors associated with death."
    supports: SUPPORT
    snippet: The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%)...
    explanation: This study lists headache as one of the main clinical signs in children with EVD, supporting the statement that headache is an occasional neurologic symptom of EVD.
  - reference: PMID:33493959
    reference_title: "Ebola: A review and focus on neurologic manifestations."
    supports: NO_EVIDENCE
    snippet: In patients with EVD, neurologic manifestations range from mild symptoms such as confusion to severe neurologic diseases such as meningitis and encephalitis. Altered mental status, from mild confusion to delirium with hallucinations, may also occur.
    explanation: Snippet does not directly mention headache.
  - reference: PMID:26983037
    reference_title: "Post-Ebola Syndrome, Sierra Leone."
    supports: SUPPORT
    snippet: Survivors reported musculoskeletal pain (70%), headache (48%), and ocular problems (14%).
    explanation: This study reports that 48% of EVD survivors experienced headaches, supporting the statement that headache is an occasional neurologic symptom of EVD.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Gastrointestinal
  frequency: FREQUENT
  name: Abdominal Pain
  evidence:
  - reference: PMID:25972150
    reference_title: "Gastrointestinal and Hepatic Manifestations of Ebola Virus Infection."
    supports: SUPPORT
    snippet: Common gastrointestinal manifestations include diarrhea-70 %, nausea and vomiting-60 %, and abdominal pain-45 %.
    explanation: The literature indicates that abdominal pain occurs in 45% of EVD cases, supporting the claim that it is a frequent gastrointestinal manifestation.
  - reference: PMID:31874716
    reference_title: "Ebola virus disease in children in Conakry and Coyah Ebola treatment centers and risk factors associated with death."
    supports: SUPPORT
    snippet: The main clinical signs were asthenia (78.8%), fever (75.3%), anorexia (53.4%), headache (45.9%), vomiting (41.8%), abdominal pain (29.5%), and diarrhea (28.8%).
    explanation: The study shows that abdominal pain was observed in 29.5% of children with EVD, supporting the statement that it is a frequent gastrointestinal symptom.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- category: Hematologic
  frequency: FREQUENT
  name: Thrombocytopenia
  sequelae:
  - target: Increased Risk of Bleeding
  evidence:
  - reference: PMID:32487785
    reference_title: "Clinical aspects of Ebola virus disease: a review."
    supports: PARTIAL
    snippet: Transmission of EBoV has been reported in various ways, including human to human transmission through close contact with blood and bodily fluids... It is usually diagnosed based on several clinical symptoms such as the sudden onset of illness, high fevers for less than three weeks, and at least two hemorrhagic symptoms despite no predisposing factors.
    explanation: The literature mentions hemorrhagic symptoms but does not specifically mention thrombocytopenia or its frequency.
  - reference: PMID:25679971
    reference_title: "Understanding bleeding in ebola virus disease."
    supports: PARTIAL
    snippet: Understanding bleeding in Ebola virus disease.
    explanation: The reference discusses bleeding in Ebola virus disease but does not specifically mention thrombocytopenia or its frequency.
  - reference: PMID:35446128
    reference_title: "Plasma Proteomic Analysis Distinguishes Severity Outcomes of Human Ebola Virus Disease."
    supports: PARTIAL
    snippet: Ebola virus (EBV) disease (EVD) is a highly virulent systemic disease characterized by an aggressive systemic inflammatory response and impaired vascular and coagulation systems, often leading to uncontrolled hemorrhaging and death.
    explanation: The literature discusses impaired vascular and coagulation systems, which can be related to thrombocytopenia, but does not specifically mention its frequency.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
- category: Hepatic
  frequency: FREQUENT
  name: Hepatitis
  sequelae:
  - target: Elevated Liver Enzymes
  - target: Impaired Liver Function
  evidence:
  - reference: PMID:2822180
    reference_title: "Viral diseases involving the liver."
    supports: PARTIAL
    snippet: Even though HAV, HBV and HNANB viruses are responsible for most of the viral hepatitis cases, many other viruses have been reported to cause hepatic injury. These viruses may involve the liver, either as part of a systemic illness (e.g. EBV, CMV, HSV) or as the primary target organ (e.g. yellow fever virus, Lassa fever virus, Ebola virus). Clinically overt hepatocellular dysfunction is rare in such viral infections.
    explanation: The reference indicates that Ebola virus can cause hepatic injury, but clinically overt hepatocellular dysfunction is rare. This partially supports the statement as it acknowledges hepatic involvement but suggests that severe liver dysfunction is not frequent.
  - reference: PMID:25972150
    reference_title: "Gastrointestinal and Hepatic Manifestations of Ebola Virus Infection."
    supports: PARTIAL
    snippet: The mean serum AST and ALT levels are each about 200/UL, with an unusual pattern for viral hepatitis of AST > ALT.
    explanation: The reference indicates elevated liver enzymes (AST and ALT) in Ebola virus infection, which supports the part of the statement regarding elevated liver enzymes. However, it does not confirm frequent impaired liver function or hepatitis as a common sequela.
  - reference: PMID:37170900
    reference_title: "Hepatic proinflammatory myeloid phenotypes are a hallmark of Ebola virus Kikwit pathogenesis in rhesus monkeys."
    supports: PARTIAL
    snippet: Results illustrate that EBOV causes macrophage phenotype alterations as well as neutrophil influx and prominent activation of interferon host responses in the liver.
    explanation: The reference provides evidence of liver involvement and immune response alterations in Ebola virus infection, which can be associated with hepatic dysfunction. However, it does not explicitly state that hepatitis or impaired liver function is frequent.
  - reference: PMID:29020340
    reference_title: "Relationship Between Viremia and Specific Organ Damage in Ebola Patients: A Cohort Study."
    supports: NO_EVIDENCE
    snippet: The role of the virus in liver damage remains unclear, but our evidence suggests that acute severe liver injury is not a typical feature of Ebola virus disease.
    explanation: The reference suggests that acute severe liver injury is not typical in Ebola virus disease, which refutes the statement that impaired liver function is frequent.
  phenotype_term:
    preferred_term: Hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
- category: Systemic
  name: Hypovolemic Shock
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypovolemic Shock
    term:
      id: HP:0031273
      label: Shock
- category: Systemic
  name: Dehydration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Metabolic
  name: Electrolyte Imbalances
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Electrolyte Imbalances
    term:
      id: HP:0003111
      label: Abnormal blood ion concentration
- name: Multiorgan Failure
  frequency: FREQUENT
  notes: HPO does not have a specific term for multiple organ dysfunction syndrome
  phenotype_term:
    preferred_term: Multiorgan Failure
- name: Elevated Liver Enzymes
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated Liver Enzymes
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
- name: Impaired Liver Function
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Impaired Liver Function
    term:
      id: HP:0001410
      label: Decreased liver function
- name: Increased Risk of Bleeding
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Increased Risk of Bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
biochemical:
- name: Ebola Virus Antigen
  presence: Positive
  assays:
  - preferred_term: Antigen-Capture Enzyme-Linked Immunosorbent Assay (ELISA)
  - preferred_term: Reverse Transcription Polymerase Chain Reaction (RT-PCR)
  evidence:
  - reference: PMID:26874083
    reference_title: "Ebola virus disease diagnosis by real-time RT-PCR: A comparative study of 11 different procedures."
    supports: PARTIAL
    snippet: The diagnosis of Ebola virus disease relies on the detection of viral RNA in blood by real-time reverse-transcription PCR.
    explanation: Supports RT-PCR RNA detection, but only partially supports antigen-specific assay claim.
  - reference: PMID:28887479
    reference_title: "Field-Effect Transistor Biosensor for Rapid Detection of Ebola Antigen."
    supports: SUPPORT
    snippet: We have developed a reduced graphene oxide-based field-effect transistor method for real-time detection of the Ebola virus antigen.
    explanation: This reference provides additional support for antigen detection methods, which indirectly supports the overall assertion.
- name: Ebola Virus RNA
  presence: Positive
  assays:
  - preferred_term: Reverse Transcription Polymerase Chain Reaction (RT-PCR)
  evidence:
  - reference: PMID:26874083
    reference_title: "Ebola virus disease diagnosis by real-time RT-PCR: A comparative study of 11 different procedures."
    supports: SUPPORT
    snippet: The diagnosis of Ebola virus disease relies on the detection of viral RNA in blood by real-time reverse-transcription PCR.
    explanation: This reference directly supports the statement that RT-PCR assays are used to detect the presence of Ebola Virus RNA.
  - reference: PMID:26465681
    reference_title: "Ebola RNA Persistence in Semen of Ebola Virus Disease Survivors - Final Report."
    supports: SUPPORT
    snippet: 'BACKGROUND: Ebola virus has been detected in the semen of men after their recovery from Ebola virus disease (EVD)... Semen specimens obtained at baseline were tested by means of a quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay...'
    explanation: This reference also supports the usage of RT-PCR assays for detecting Ebola Virus RNA in biological samples.
environmental:
- name: Animal Reservoirs
  notes: Fruit bats are considered the natural hosts; transmission also occurs through handling of infected wild animals.
  evidence:
  - reference: PMID:17848072
    reference_title: "Ebolavirus and other filoviruses."
    supports: SUPPORT
    snippet: 'Among the various animals captured and analyzed, three species of fruit bats (suborder Megachiroptera) were found asymptomatically and naturally infected with Ebola virus: Hypsignathus monstrosus (hammer-headed fruit beats), Epomops franqueti (singing fruit bats), and Myonycteris torquata (little collared fruit bats)'
    explanation: This study confirms that certain species of fruit bats serve as Ebola virus reservoirs, supporting the notion that fruit bats are natural hosts of the virus.
  - reference: PMID:28573636
    reference_title: "Ebola Virus Field Sample Collection."
    supports: PARTIAL
    snippet: Although an ebolavirus natural reservoir has yet to be identified, the majority of disease ecologists believe the reservoir to belong to the order Chiroptera (bats).
    explanation: While bats are strongly suspected to be the natural reservoir, the virus has not been isolated definitively from them, providing partial but not conclusive support.
  - reference: PMID:26757869
    reference_title: "[Ebola: characterization, history and cutaneous manifestations]."
    supports: SUPPORT
    snippet: Fruits bats are its natural reservoir, the transmission to humans is across wild animals (especially primates) and the propagation in human populations is through bodily fluid contact
    explanation: This literature indicates that fruit bats are considered the natural reservoir for Ebola, supporting the statement.
  - reference: PMID:26147380
    reference_title: "Ebola virus disease: societal challenges and new treatments."
    supports: PARTIAL
    snippet: Ebola virus disease (EVD) is a zoonotic disease that causes severe haemorrhagic fever, with high fatality rates of up to 90% in humans.
    explanation: Supports zoonotic nature, but only partially supports specific fruit-bat reservoir assertion.
  exposure_term:
    preferred_term: Animal reservoir exposure
    term:
      id: ECTO:3000001
      label: exposure to virus
pathophysiology:
- name: Viral Entry via Endocytosis
  description: Ebola virus enters host cells through receptor-mediated macropinocytosis. The virus attaches to phosphatidylserine receptors like TIM-1 (HAVCR1) and is internalized into endosomes. Cathepsins B and L cleave the viral glycoprotein (GP), followed by binding to the essential receptor NPC1 in late endosomes/lysosomes, triggering membrane fusion and release of viral genome into the cytoplasm.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  notes: NPC1, HAVCR1 (TIM-1), SLC39A9, PIK3C3, and cathepsins are critical host factors. The process depends on macropinocytosis and late endosomal cholesterol transport.
- name: Immune Evasion and Viral Replication
  description: Ebola viral proteins VP35 and VP24 antagonize the host interferon response. VP35 binds dsRNA and blocks RIG-I signaling, while VP24 prevents STAT1 nuclear import, thereby suppressing type I interferon signaling. This allows rapid viral replication and high viremia in infected monocytes, macrophages, and dendritic cells.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  notes: VP35 and VP24 are multifunctional proteins that integrate polymerase cofactor roles with immune evasion. Secreted GP (sGP) may act as an antibody decoy.
- name: Endothelial Dysfunction and Vascular Leak
  description: Ebola virus glycoprotein (GP) and secreted GP (sGP) contribute to endothelial cell activation and barrier disruption. This leads to increased vascular permeability, fluid extravasation, and hypovolemic shock. Endothelial dysfunction is a central feature of Ebola hemorrhagic fever.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  notes: GP-mediated endothelial perturbations and inflammatory signaling drive shock in viral hemorrhagic fevers. Glycocalyx disruption and loss of adherens junction integrity contribute to vascular leak.
- name: Coagulopathy and Disseminated Intravascular Coagulation
  description: Ebola infection triggers systemic inflammatory response with cytokine release, endothelial activation, and tissue factor pathway activation. This leads to thromboinflammation, platelet activation, consumptive coagulopathy, and disseminated intravascular coagulation (DIC), resulting in hemorrhagic manifestations.
  biological_processes:
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  notes: Impaired coagulation systems with uncontrolled hemorrhaging characterize severe EVD. Thrombocytopenia and elevated liver enzymes are common laboratory findings.
- name: Multiorgan Involvement
  description: Ebola virus infects multiple organs including liver, spleen, lymph nodes, and kidneys. Hepatic dysfunction with elevated liver enzymes (AST > ALT pattern) and splenic involvement contribute to multiorgan failure in severe cases.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: spleen
    term:
      id: UBERON:0002106
      label: spleen
  notes: Liver involvement manifests with elevated AST and ALT (unusual AST > ALT pattern). Macrophage activation and cytokine storm contribute to organ damage.
treatments:
- name: Supportive Care
  description: Includes rehydration, symptomatic treatment to manage fever, bleeding, and pain.
  evidence:
  - reference: PMID:37355146
    reference_title: "Ebola virus disease: A narrative review."
    supports: SUPPORT
    snippet: Early detection and supportive care can enhance the likelihood of survival. This includes intravenous fluids, electrolyte replacement, and treatment of secondary infections.
    explanation: The provided literature supports that supportive care, including rehydration and symptomatic treatment, is a key component in the treatment of Ebola Virus Disease (EVD).
  - reference: PMID:28646340
    reference_title: "Clinical Management of Ebola Virus Disease Patients in Low-Resource Settings."
    supports: SUPPORT
    snippet: Clinical management of EVD combines supportive and symptomatic care while also addressing the patient's emotional and mental health needs.
    explanation: This literature indicates the combination of supportive and symptomatic care is part of the clinical management of EVD.
  - reference: PMID:29054555
    reference_title: "Evidence-based guidelines for supportive care of patients with Ebola virus disease."
    supports: SUPPORT
    snippet: Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief.
    explanation: The evidence-based guidelines for supportive care of patients with EVD include recommendations that align with rehydration and symptomatic treatments for managing fever, bleeding, and pain.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Experimental Therapies
  description: Includes antiviral drugs, immune therapies, and blood products from survivors containing antibodies.
  evidence:
  - reference: PMID:27337455
    reference_title: "Ebola Virus Disease: Therapeutic and Potential Preventative Opportunities."
    supports: SUPPORT
    snippet: The armamentarium against EVD eventually included biologics such as monoclonal antibodies, convalescent plasma, and vaccines as well as small molecule therapeutics such as small interfering RNAs and nucleoside analogs.
    explanation: The reference mentions the use of various experimental therapies including immune therapies (monoclonal antibodies), blood products (convalescent plasma), and small molecule therapeutics (antiviral drugs).
  - reference: PMID:11766882
    reference_title: "Ebola virus: the search for vaccines and treatments."
    supports: PARTIAL
    snippet: This review describes Ebola viruses, with a particular focus on the status of research efforts to develop vaccines and therapeutics and to identify the immune mechanisms of protection.
    explanation: Supports historical therapeutic research context, but only partially supports specific experimental therapy modalities.
  - reference: PMID:25457751
    reference_title: "Ebola virus convalescent blood products: where we are now and where we may need to go."
    supports: SUPPORT
    snippet: Recently, the use of convalescent blood products was proposed by the WHO as one early option for treating patients with Ebola virus disease.
    explanation: The reference confirms the use of convalescent blood products as a treatment strategy for EVD, supporting the statement.
  - reference: PMID:32487785
    reference_title: "Clinical aspects of Ebola virus disease: a review."
    supports: SUPPORT
    snippet: 'Management of patients involves supportive care such as maintaining fluid along with electrolyte balance, blood pressure and oxygen saturation. This also includes treating complications arising from secondary infections. The main options include: prophylactic strategies, anti-viral therapy for EVD, immunotherapies, vaccines, and ZMapp.'
    explanation: The reference lists anti-viral therapy and immunotherapies as main treatment options, confirming the statement's reference to experimental therapies.
  - reference: PMID:30943399
    reference_title: "Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans."
    supports: SUPPORT
    snippet: We describe therapeutic monoclonal antibodies isolated from human volunteers vaccinated with recombinant adenovirus expressing Ebola virus glycoprotein (EBOV GP).
    explanation: The reference discusses therapeutic monoclonal antibodies, which are a form of immune therapy, in line with the statement.
  treatment_term:
    preferred_term: antiviral agent therapy
    term:
      id: MAXO:0000168
      label: antiviral agent therapy
- name: Vaccination
  description: The rVSV-ZEBOV vaccine has been shown to be effective in preventing Ebola infection.
  evidence:
  - reference: PMID:28017403
    reference_title: "Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)."
    supports: SUPPORT
    snippet: The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.
    explanation: The study shows that rVSV-ZEBOV vaccine offers substantial protection against Ebola virus disease, supporting the statement that it is effective in preventing Ebola infection.
  - reference: PMID:32243796
    reference_title: "A Vaccine against Ebola Virus."
    supports: SUPPORT
    snippet: Ervebo is the first licensed vaccine for prevention of Ebola virus disease.
    explanation: The article states that Ervebo (rVSV-ZEBOV) is licensed for the prevention of Ebola virus disease, supporting the statement that the vaccine is effective in preventing Ebola infection.
  - reference: PMID:33873076
    reference_title: "Ebola virus disease: current vaccine solutions."
    supports: SUPPORT
    snippet: 'Currently, two vaccines: Ervebo (rVSV-ZEBOV) and a two-dose combination of Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) have been licensed and in use.'
    explanation: The abstract mentions that Ervebo (rVSV-ZEBOV) has been licensed and is being used to prevent Ebola Virus Disease, supporting the statement that it is effective in preventing infection.
  - reference: PMID:34749265
    reference_title: "Therapeutic vaccination strategies against EBOV by rVSV-EBOV-GP: the role of innate immunity."
    supports: SUPPORT
    snippet: In 2019, the FDA-approved the first anti-EBOV vaccine, rVSV-EBOV-GP (Ervebo® by Merck)
    explanation: The article confirms that the rVSV-EBOV-GP (Ervebo) vaccine is FDA-approved and provides prophylactic protection against Ebola, supporting the statement that it is effective in preventing Ebola infection.
  treatment_term:
    preferred_term: vaccination
    term:
      id: MAXO:0001017
      label: vaccination
genetic:
- name: NPC1
  association: Host factor
  notes: Niemann-Pick C1 protein is a late endosomal/lysosomal cholesterol transporter that serves as the essential receptor for Ebola virus GP-mediated membrane fusion and cytosolic entry. Genetic depletion blocks EBOV entry.
- name: HAVCR1
  association: Host factor
  notes: Hepatitis A virus cellular receptor 1 (TIM-1) is a phosphatidylserine receptor that serves as an attachment factor for Ebola virus, facilitating viral entry into host cells.
- name: SLC39A9
  association: Host factor
  notes: Zinc transporter protein identified by CRISPR screen as a crucial entry factor for Ebola virus. Impacts glycosylation processes required for viral internalization.
- name: PIK3C3
  association: Host factor
  notes: Class III phosphatidylinositol 3-kinase (VPS34) identified by CRISPR screen as essential for EBOV entry. Its kinase activity is indispensable for the internalization of Ebola virions through macropinocytosis.
- name: CTSB
  association: Host factor
  notes: Cathepsin B is an endosomal protease that primes Ebola virus glycoprotein (GP) for receptor binding and membrane fusion in late endosomes.
- name: CTSL
  association: Host factor
  notes: Cathepsin L is an endosomal protease that primes Ebola virus glycoprotein (GP) for receptor binding and membrane fusion in late endosomes.
review_notes: Ebola is a severe viral hemorrhagic fever. Key features are the sudden onset of fever, muscle pain, headache and sore throat, followed by vomiting, diarrhea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Mortality is high. Transmission occurs through direct contact with bodily fluids of infected people or animals.
disease_term:
  preferred_term: Ebola hemorrhagic fever
  term:
    id: MONDO:0005737
    label: Ebola hemorrhagic fever
📚

References & Deep Research

Deep Research

2
Disorder ▸

Disorder

  • Name: Ebola Virus Disease (EVD)
  • Category:
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 76

Key Pathophysiology Nodes

  • Viral Entry via Endocytosis
  • Immune Evasion and Viral Replication
  • Endothelial Dysfunction and Vascular Leak
  • Coagulopathy and Disseminated Intravascular Coagulation
  • Multiorgan Involvement
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/s2666-5247(23
  • DOI:10.1038/s41392-024-01917-x
  • DOI:10.1101/2024.03.20.24304571
  • DOI:10.1186/s43042-024-00600-8
  • DOI:10.1371/journal.ppat.1012038
  • DOI:10.1371/journal.ppat.1012444
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 15 citations 2025-12-15T09:20:22.100697

Disease Pathophysiology Research Report

Target Disease - Disease Name: Ebola Virus Disease (EVD) - MONDO ID: MONDO:0005737 - Category: Viral hemorrhagic fever (Filoviridae)

  1. Core Pathophysiology
  2. Primary mechanisms: Ebola virus (EBOV) initiates infection by attachment and macropinocytic uptake into endosomes, proteolytic priming of GP by cathepsins, and obligatory engagement of the late endosomal/lysosomal cholesterol transporter Niemann–Pick C1 (NPC1) to trigger membrane fusion and cytosolic entry. Genetic screens newly identified SLC39A9 and PIK3C3 as host factors facilitating entry/internalization, complementing established roles for TIM‑1/HAVCR1 and C‑type lectins as attachment factors and macropinocytosis as the uptake route (PLOS Pathogens, Aug 22, 2024; https://doi.org/10.1371/journal.ppat.1012444). “Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry… PIK3C3 kinase activity is indispensable for the internalization of EBOV virions” (excerpt) (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30).
  3. Immune evasion and replication: VP35 binds dsRNA and functions as polymerase cofactor, antagonizing RIG‑I signaling; VP24 antagonizes IFN signaling via karyopherin‑α/STAT1 nuclear import and contributes to nucleocapsid assembly; GP mediates entry and its secreted isoform (sGP) modulates immunity and can act as an antibody decoy; VP40 and NP structure the virion and nucleocapsid (Egyptian Journal of Medical Human Genetics, Nov 2024; https://doi.org/10.1186/s43042-024-00600-8) (ndayambaje2024molecularcharacterizationof pages 1-2).
  4. Endothelial dysfunction/vascular leak: EBOV GP and shed/sG P are implicated in endothelial activation, barrier disruption, and vascular leak; reviews highlight GP-driven endothelial perturbations and sGP-mediated immune modulation; endothelial barrier failure integrates with inflammatory signaling to drive shock in VHFs (Signal Transduct Target Ther, Sep 2024; https://doi.org/10.1038/s41392-024-01917-x) (wang2024emergingandreemerging pages 53-53).
  5. Coagulopathy/DIC: Ebola belongs to VHFs characterized by thromboinflammation—cytokine-driven endothelial activation, tissue factor pathway triggering, platelet activation—culminating in consumptive coagulopathy and bleeding (overview) (Signal Transduct Target Ther, Sep 2024; https://doi.org/10.1038/s41392-024-01917-x) (wang2024emergingandreemerging pages 53-53).

  6. Disease course/epidemiology: Meta-analysis of EVD parameters (publications up to July 7, 2023) estimated pooled incubation period 8.5 days (95% CI 7.7–9.2), serial interval 15.4 days (95% CI 13.2–17.5), symptom onset-to-death 9.3 days (95% CI 8.5–10.1), onset-to-recovery 13.0 days (95% CI 10.4–15.7); CFR is high and heterogeneous across species and contexts (MedRxiv, Mar 21, 2024; https://doi.org/10.1101/2024.03.20.24304571) (nash2024ebolavirusdisease pages 25-27).

  7. Key Molecular Players

  8. Genes/Proteins (HGNC):
  9. NPC1 (HGNC:14930): endo/lysosomal receptor essential for EBOV fusion/entry (PLOS Pathogens, Mar 15, 2024; https://doi.org/10.1371/journal.ppat.1012038) (ayoubi2024recentadvancesin pages 6-8).
  10. HAVCR1/TIM‑1 (HGNC:16064): phosphatidylserine receptor serving as EBOV attachment/cofactor (PLOS Pathogens, Aug 22, 2024; https://doi.org/10.1371/journal.ppat.1012444) (gong2024genomewidecrisprcas9screen pages 25-26).
  11. SLC39A9 (HGNC:18018): zinc transporter impacting glycosylation; CRISPR hit promoting EBOV entry (PLOS Pathogens, Aug 22, 2024; https://doi.org/10.1371/journal.ppat.1012444) (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30).
  12. PIK3C3/VPS34 (HGNC:8975): class III PI3K; CRISPR hit; kinase activity required for virion internalization (PLOS Pathogens, Aug 22, 2024) (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30).
  13. Cathepsins (e.g., CTSB/CTSL): endosomal proteases priming GP (PLOS Pathogens, Aug 22, 2024) (gong2024genomewidecrisprcas9screen pages 25-26).
  14. EBOV GP (glycoprotein; gene GP): mediates receptor binding/fusion; sGP immune decoy (Egyptian J Med Hum Genet, Nov 2024; PLOS Pathogens, Mar 15, 2024) (ndayambaje2024molecularcharacterizationof pages 1-2, ayoubi2024recentadvancesin pages 6-8).
  15. VP35 (gene VP35): dsRNA-binding; polymerase cofactor; IFN antagonist (Egyptian J Med Hum Genet, Nov 2024) (ndayambaje2024molecularcharacterizationof pages 1-2).
  16. VP24 (gene VP24): interferon antagonism via karyopherin‑α/STAT1 blockade; nucleocapsid assembly (Egyptian J Med Hum Genet, Nov 2024) (ndayambaje2024molecularcharacterizationof pages 1-2).
  17. NP (nucleoprotein), L (RNA-dependent RNA polymerase), VP30, VP40: nucleocapsid and assembly (Egyptian J Med Hum Genet, Nov 2024) (ndayambaje2024molecularcharacterizationof pages 1-2).
  18. Chemical entities (ChEBI):
  19. Small-molecule NPC1 inhibitors (e.g., MBX2254/MBX2270; diaryl sulfides SC198/SC073/SC816) targeting NPC1-GP interaction; clomiphene and other GP-directed entry inhibitors discussed (PLOS Pathogens, Mar 15, 2024) (ayoubi2024recentadvancesin pages 6-8).
  20. Cell Types (CL):
  21. Monocytes/macrophages (CL:0000576/CL:0000235), dendritic cells (CL:0000451): early targets/immune dysregulation (Egyptian J Med Hum Genet, Nov 2024) (ndayambaje2024molecularcharacterizationof pages 1-2).
  22. Endothelial cells (CL:0000115): barrier dysfunction/vascular leak (Signal Transduct Target Ther, Sep 2024) (wang2024emergingandreemerging pages 53-53).
  23. Anatomical Locations (UBERON):

  24. Liver (UBERON:0002107), spleen (UBERON:0002106), vasculature/endothelium (UBERON:0001981): organ injury and vascular pathology in VHFs (Signal Transduct Target Ther, Sep 2024; Egyptian J Med Hum Genet, Nov 2024) (wang2024emergingandreemerging pages 53-53, ndayambaje2024molecularcharacterizationof pages 1-2).

  25. Biological Processes (GO) disrupted

  26. Viral entry via endocytosis/macropinocytosis; endosomal proteolysis; membrane fusion (GO:0046718, GO:0006907, GO:0007010 proxy for macropinocytosis). Supported by CRISPR/host factor data (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30).
  27. Negative regulation of type I interferon signaling (GO:0060338) by VP24/VP35 (ndayambaje2024molecularcharacterizationof pages 1-2).
  28. Innate immune response to dsRNA (GO:0039529) antagonized by VP35 (ndayambaje2024molecularcharacterizationof pages 1-2).
  29. Endothelial cell activation and increased permeability (GO:0001936, GO:0043114) in VHFs; sGP/GP-linked effects (wang2024emergingandreemerging pages 53-53).

  30. Blood coagulation and extrinsic pathway (GO:0007596; GO: extrinsic pathway of coagulation) leading to DIC in VHFs (wang2024emergingandreemerging pages 53-53).

  31. Cellular Components

  32. Late endosome/lysosome membrane (GO:0031902/GO:0005765) where NPC1 mediates GP-dependent fusion (ayoubi2024recentadvancesin pages 6-8).
  33. Viral inclusion bodies and nucleocapsid (GO:0019013; viral nucleocapsid) for replication and immune evasion (ndayambaje2024molecularcharacterizationof pages 1-2).

  34. Endothelial adherens junctions/glycocalyx (GO:0005912; extracellular region) implicated in vascular permeability (wang2024emergingandreemerging pages 53-53).

  35. Disease Progression (sequence of events)

  36. Exposure and incubation (median ~8–9 days) followed by abrupt febrile illness; early infection of monocytes/macrophages/DCs promotes high viremia and IFN antagonism (nash2024ebolavirusdisease pages 25-27, ndayambaje2024molecularcharacterizationof pages 1-2).
  37. Amplifying inflammation with endothelial activation, GP/sGP-mediated barrier dysfunction, and coagulopathy; clinical progression to hypovolemia, shock, and multiorgan failure (wang2024emergingandreemerging pages 53-53).

  38. Outcome trajectories: fatal cases with rapid onset-to-death (~9 days); survivors recover ~13 days from symptom onset (medians), reflecting heterogeneous host responses and care (nash2024ebolavirusdisease pages 25-27).

  39. Phenotypic Manifestations (HP terms)

  40. Acute febrile illness (HP:0001945), hemorrhage/bleeding (HP:0001091), thrombocytopenia (HP:0001873), hypotension (HP:0002615), shock (HP:0001943), hepatic dysfunction (HP:0001410), diarrhea/vomiting (HP:0002014/HP:0002013), neurologic symptoms (HP:0001297), conjunctival injection/rash (HP:0000532/HP:0000988). Mechanistic linkage to vascular leak/coagulopathy and immune dysregulation (wang2024emergingandreemerging pages 53-53, ndayambaje2024molecularcharacterizationof pages 1-2, nash2024ebolavirusdisease pages 25-27).

  41. Recent Developments and Implementations (2023–2024)

  42. Therapeutics: Two monoclonal antibody products—REGN‑EB3 (Inmazeb) and mAb114 (Ansuvimab/Ebanga)—are FDA‑approved and remain the only licensed EVD therapeutics; continued development targets broader neutralization across species and combination strategies; entry inhibitors (NPC1‑targeting small molecules) and host‑directed agents (AAK1 inhibitors) are under study; “Monoclonal antibodies remain the only FDA‑approved therapeutics…”; secreted GP can act as a decoy reducing mAb efficacy, motivating multi‑epitope cocktails (PLOS Pathogens, Mar 15, 2024; https://doi.org/10.1371/journal.ppat.1012038) (ayoubi2024recentadvancesin pages 6-8).
  43. Vaccines: rVSV‑ZEBOV (Ervebo) is FDA/WHO prequalified and used operationally (ring vaccination); heterologous Ad26.ZEBOV/MVA‑BN‑Filo regimen shows robust immunogenicity and age‑stratified responses; antibody kinetics differ by platform, with rVSV showing less‑rapid decline and children maintaining higher titers in modeling; “participants receiving a delayed dose 2 had a higher GMC… than standard 56‑day regimen” (example from implementation literature cited within) (PLOS Pathogens, Mar 15, 2024; MedRxiv meta‑analysis context) (ayoubi2024recentadvancesin pages 6-8, nash2024ebolavirusdisease pages 25-27).

  44. Occupational exposure guidance: Clinical guidance highlights availability of mAbs and ring vaccination approaches for post‑exposure risk contexts (summarized in 2024 overview) (PLOS Pathogens, Mar 15, 2024) (ayoubi2024recentadvancesin pages 6-8).

  45. Epidemiology and Statistics (recent meta-analysis/outbreak reports)

  46. Incubation period: pooled 8.5 days (95% CI 7.7–9.2) (MedRxiv, Mar 21, 2024; https://doi.org/10.1101/2024.03.20.24304571) (nash2024ebolavirusdisease pages 25-27).
  47. Serial interval: pooled 15.4 days (95% CI 13.2–17.5) (nash2024ebolavirusdisease pages 25-27).
  48. Symptom onset-to-death: pooled 9.3 days (95% CI 8.5–10.1); onset-to-recovery 13.0 days (95% CI 10.4–15.7) (nash2024ebolavirusdisease pages 25-27).
  49. Case fatality ratio (CFR): ranges widely by species/outbreak (e.g., Zaire, Sudan, Bundibugyo), reflecting heterogeneity in strain, care, and demographics; meta‑analysis describes extensive variability (nash2024ebolavirusdisease pages 25-27). Example: Equateur Province 2020 outbreak CFR ~42% (The Lancet Microbe 2024, retrospective characterization; Feb 2024; https://doi.org/10.1016/S2666-5247(23)00259-8) (nash2024ebolavirusdisease pages 25-27).

Expert Commentary and Analysis - Entry biology has matured from a single‑receptor (NPC1) paradigm to a multistep continuum: initial attachment via TIM‑1/lectins and PS‑mediated interactions, GP‑dependent macropinocytosis, cathepsin priming, and NPC1 engagement as the essential fusion checkpoint. The 2024 CRISPR study identifying SLC39A9 and PIK3C3 as crucial entry factors extends this model toward glycan regulation and PI3K‑dependent endocytic trafficking as druggable host nodes (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30). - Immune evasion hinges on multifunctional proteins: VP35 integrates polymerase cofactor function with dsRNA sequestration; VP24 concurrently shapes nucleocapsid assembly and disrupts STAT1 nuclear import, undermining IFN signaling; GP and sGP diversify immune modulation and may reduce therapeutic mAb effectiveness, supporting multi‑epitope antibody strategies and small‑molecule entry inhibitors (ndayambaje2024molecularcharacterizationof pages 1-2, ayoubi2024recentadvancesin pages 6-8). - Vascular pathobiology remains central to fatal EVD. Cross‑VHF evidence supports a model of endothelial activation, glycocalyx disruption, and increased permeability, compounded by coagulopathy and hypovolemia; GP/sGP likely contribute to endothelial dysfunction, while thromboinflammation and tissue factor drive DIC phenotypes in severe disease (wang2024emergingandreemerging pages 53-53). - Implementation: mAb therapeutics have improved survival yet leave residual mortality; ensuring timely access and integrating supportive care remain critical. Vaccine platforms provide complementary options: rVSV for rapid ring vaccination and Ad26/MVA for durable heterologous immunity; durability modeling and age‑dependent immunogenicity inform booster and deployment strategies (ayoubi2024recentadvancesin pages 6-8, nash2024ebolavirusdisease pages 25-27).

Direct evidence quotes - “Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry… PIK3C3 kinase activity is indispensable for the internalization of EBOV virions” (PLOS Pathogens, Aug 22, 2024; https://doi.org/10.1371/journal.ppat.1012444) (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30). - “Monoclonal antibodies remain the only FDA‑approved therapeutics… secreted GP may act as a decoy reducing mAb efficacy; escape variants motivate multi‑epitope antibody cocktails” (PLOS Pathogens, Mar 15, 2024; https://doi.org/10.1371/journal.ppat.1012038) (ayoubi2024recentadvancesin pages 6-8).

Ontology Annotations (selected; with supporting citations for mechanistic linkage) - Genes/Proteins (HGNC): NPC1; HAVCR1; SLC39A9; PIK3C3; CTSB/CTSL; GP; VP24; VP35; NP; L; VP30; VP40 (gong2024genomewidecrisprcas9screen pages 25-26, ndayambaje2024molecularcharacterizationof pages 1-2, gong2024genomewidecrisprcas9screen pages 29-30, ayoubi2024recentadvancesin pages 6-8). - Biological Process (GO): viral entry via endocytosis/macropinocytosis; endosomal proteolysis; membrane fusion; negative regulation of type I IFN signaling; endothelial cell permeability; blood coagulation (gong2024genomewidecrisprcas9screen pages 25-26, ndayambaje2024molecularcharacterizationof pages 1-2, wang2024emergingandreemerging pages 53-53, gong2024genomewidecrisprcas9screen pages 29-30). - Cellular Component (GO): late endosome/lysosome membrane; viral nucleocapsid; endothelial cell-cell junction; endothelial glycocalyx/extracellular region (ayoubi2024recentadvancesin pages 6-8, ndayambaje2024molecularcharacterizationof pages 1-2, wang2024emergingandreemerging pages 53-53). - Cell Types (CL): monocytes/macrophages; dendritic cells; endothelial cells (ndayambaje2024molecularcharacterizationof pages 1-2, wang2024emergingandreemerging pages 53-53). - Anatomical Sites (UBERON): liver; spleen; vasculature/endothelium (wang2024emergingandreemerging pages 53-53, ndayambaje2024molecularcharacterizationof pages 1-2). - Chemical Entities (ChEBI): NPC1-targeting small molecules; GP entry inhibitors (ayoubi2024recentadvancesin pages 6-8). - Phenotypes (HP): hemorrhage, thrombocytopenia, shock, hepatic dysfunction, gastrointestinal symptoms (wang2024emergingandreemerging pages 53-53, nash2024ebolavirusdisease pages 25-27).

Current Applications and Real‑World Implementations (with URLs/dates) - Therapeutic mAbs: Inmazeb (REGN‑EB3) and Ebanga (Ansuvimab/mAb114) in clinical use; continued work on pan‑ebolavirus mAbs and combinations (PLOS Pathogens, Mar 15, 2024; https://doi.org/10.1371/journal.ppat.1012038) (ayoubi2024recentadvancesin pages 6-8). - Vaccination: rVSV‑ZEBOV ring vaccination in outbreak control; Ad26.ZEBOV/MVA‑BN‑Filo immunogenicity and durability modeling to inform booster policies (PLOS Pathogens, Mar 15, 2024; MedRxiv Mar 21, 2024) (ayoubi2024recentadvancesin pages 6-8, nash2024ebolavirusdisease pages 25-27). - Host‑targeted entry inhibitors (NPC1, AAK1) and AI‑driven repurposing pipelines are under investigation to complement antibody therapy (PLOS Pathogens, Mar 15, 2024) (ayoubi2024recentadvancesin pages 6-8).

Evidence items (with PMIDs/DOIs/URLs) - Ayoubi et al., Recent advances in the treatment of Ebola disease: A brief overview. PLOS Pathogens. Mar 15, 2024. DOI: 10.1371/journal.ppat.1012038. URL: https://doi.org/10.1371/journal.ppat.1012038 (mechanisms, therapeutics, vaccines, NPC1 targeting) (ayoubi2024recentadvancesin pages 6-8). - Gong et al., Genome-wide CRISPR/Cas9 screen identifies SLC39A9 and PIK3C3 as crucial entry factors for Ebola virus infection. PLOS Pathogens. Aug 22, 2024. DOI: 10.1371/journal.ppat.1012444. URL: https://doi.org/10.1371/journal.ppat.1012444 (entry host factors, macropinocytosis/cathepsins/NPC1 pathway context) (gong2024genomewidecrisprcas9screen pages 25-26, gong2024genomewidecrisprcas9screen pages 29-30). - Ndayambaje et al., Molecular characterization of Ebola virus, immune response, and therapeutic challenges. Egyptian Journal of Medical Human Genetics. Nov 2024. DOI: 10.1186/s43042-024-00600-8. URL: https://doi.org/10.1186/s43042-024-00600-8 (viral proteins and immune evasion overview; sGP) (ndayambaje2024molecularcharacterizationof pages 1-2). - Wang et al., Emerging and reemerging infectious diseases: global trends and new strategies for their prevention and control. Signal Transduct Target Ther. Sep 2024. DOI: 10.1038/s41392-024-01917-x. URL: https://doi.org/10.1038/s41392-024-01917-x (vascular dysfunction/endothelial injury in VHFs; sGP and GP endothelial effects referenced) (wang2024emergingandreemerging pages 53-53). - Nash et al., Ebola Virus Disease mathematical models and epidemiological parameters: a systematic review and meta-analysis. MedRxiv. Mar 21, 2024. DOI: 10.1101/2024.03.20.24304571. URL: https://doi.org/10.1101/2024.03.20.24304571 (incubation, serial interval, onset-to-death/recovery, CFR ranges; example DRC Equateur 2020 CFR) (nash2024ebolavirusdisease pages 25-27).

Limitations and open questions - Direct, human in vivo mechanistic evidence for endothelial glycocalyx injury markers (e.g., syndecan‑1) specific to Ebola in 2023–2024 sources is less abundant in the retrieved set; however, cross‑VHF vascular leak paradigms and EBOV GP/sGP endothelial effects are supported in recent reviews (wang2024emergingandreemerging pages 53-53). Further targeted clinical studies in EVD cohorts would refine causal pathways.

Conclusion EVD pathophysiology reflects a convergence of: (i) multistep entry culminating in NPC1‑dependent fusion and newly defined host entry nodes (SLC39A9, PIK3C3); (ii) potent viral antagonism of type I IFN and immune sensing by VP24/VP35; (iii) endothelial dysfunction with vascular leak and thromboinflammation leading to DIC; and (iv) rapid clinical trajectories with high CFR variability. Recent advances in therapeutics (licensed mAbs) and vaccines (rVSV‑ZEBOV; Ad26.ZEBOV/MVA‑BN‑Filo) have improved outcomes and outbreak control, while host‑directed entry inhibitors and broader mAb strategies aim to further reduce mortality and expand cross‑species protection (gong2024genomewidecrisprcas9screen pages 25-26, ndayambaje2024molecularcharacterizationof pages 1-2, wang2024emergingandreemerging pages 53-53, ayoubi2024recentadvancesin pages 6-8, nash2024ebolavirusdisease pages 25-27).

References

  1. (gong2024genomewidecrisprcas9screen pages 25-26): Mingli Gong, Cheng Peng, Chen Yang, Zhenhua Wang, Hongwu Qian, Xue Hu, Peng Zhou, Chao Shan, and Qiang Ding. Genome-wide crispr/cas9 screen identifies slc39a9 and pik3c3 as crucial entry factors for ebola virus infection. PLOS Pathogens, 20:e1012444, Aug 2024. URL: https://doi.org/10.1371/journal.ppat.1012444, doi:10.1371/journal.ppat.1012444. This article has 7 citations and is from a highest quality peer-reviewed journal.

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