Ebola Virus (EBOV)
Filamentous enveloped negative-sense ssRNA virus (~19 kb; 7 genes in 3′→5′ order: NP–VP35–VP40–GP–VP30–VP24–L). The sole surface antigen, the GP1,2 trimeric spike, mediates entry via macropinocytosis and cathepsin B/L-dependent cleavage in late endosomes to expose the NPC1 (Niemann-Pick C1) receptor-binding domain — an obligate intracellular receptor unique among human viral pathogens. VP40 (matrix protein) drives virion budding and filamentous morphology. Pathogenicity arises from a coordinated dual immune evasion: VP35 blocks RIG-I/MDA5-mediated IFN-β production; VP24 prevents STAT1 nuclear import, blocking IFN-JAK-STAT signalling. Secreted sGP (soluble GP decoy) absorbs neutralising antibodies; infected macrophages/DCs release massive cytokine storms (TNF-α, IL-6, IL-1β) while failing to prime adaptive T-cell responses. The terminal common pathway is multi-organ failure from vascular leak, DIC, and hepatic necrosis rather than exsanguination per se.
Classification & Structure
| Genome | ~19 kb negative-sense single-stranded RNA (−ssRNA); non-segmented; 7 genes in 3′→5′ order: NP, VP35, VP40, GP, VP30, VP24, L (RNA-dependent RNA polymerase). Must be transcribed to +sense mRNAs before translation — L polymerase bundled in nucleocapsid. |
| Family / Genus | Filoviridae / Ebolavirus. Species: Zaire ebolavirus (most lethal; responsible for all major outbreaks). Other species: Sudan, Bundibugyo, Taï Forest, Reston (non-pathogenic in humans), Bombali. |
| Envelope | Yes — host-derived lipid bilayer; GP1,2 trimeric spikes (~10 nm projections) are the sole surface antigen; VP40 major matrix protein lines inner leaflet and drives budding |
| Size / morphology | ~80 nm diameter, uniformly; 800–1,000 nm length (typical infectious unit ~805 nm); characteristic filamentous "shepherd’s crook" or loop shape by electron microscopy; some virions reach 14,000 nm in length |
| Genotypes | Makona (2014–2016 West Africa — accumulated >600 fixed mutations), Kikwit (1995 DRC), Mayinga (1976 DRC). No clinically distinct serotypes; all strains antigenically cross-reactive. |
| Key virulence factors | GP1,2 (entry + sGP antibody decoy); VP35 (IFN-β production block via RIG-I/IRF3 inhibition); VP24 (STAT1 nuclear import block); VP40 (budding, tetherin/BST-2 antagonist); NP (innate immune suppression) |
Infection Mechanism
1 · Contact transmission and primary target cells
EBOV is transmitted exclusively by direct contact with blood, secretions, or organs of infected persons — no aerosol transmission documented in natural outbreaks. Healthcare workers, burial teams, and close family caregivers face highest risk. The natural reservoir is most likely insectivorous fruit bats (Rousettus aegyptiacus). Upon exposure, macrophages and dendritic cells are the primary early cellular targets, expressing DC-SIGN (CD209) and L-SIGN (CD209L) — high-affinity attachment factors for GP1.
2 · Macropinocytosis and endosomal entry via NPC1
EBOV triggers large-scale macropinocytosis (actin-driven membrane ruffling, forming ~0.5–5 µm vesicles) as its primary internalization route. Within the late endosome/lysosome, host cathepsins B and L proteolytically cleave GP1 from ~130 kDa to a ~19 kDa core fragment, exposing the NPC1 (Niemann-Pick C1) receptor-binding domain. NPC1 is a late endosomal cholesterol transporter; its discovery as EBOV’s intracellular receptor (Carette et al., Nature 2011) explained EBOV’s broad cellular tropism and opened cathepsin/NPC1 as drug targets.
3 · Membrane fusion, replication, and VP40-driven budding
NPC1 engagement triggers GP2 conformational change: the internal fusion peptide inserts into the endosomal membrane, driving six-helix-bundle formation and lipid bilayer merging — releasing the nucleocapsid. The L polymerase transcribes 7 capped, polyadenylated mRNAs. Replication occurs in perinuclear inclusion bodies (viral factories) visible by EM. New nucleocapsids are transported to the plasma membrane; VP40 drives actin-dependent budding into the filamentous progeny virion shape.
4 · VP35 blocks IFN-β production at the RIG-I level
VP35 is a dsRNA-binding protein that competitively inhibits RIG-I and MDA5 from recognising viral dsRNA replication intermediates. VP35 also directly blocks IRF3 and IRF7 phosphorylation and nuclear translocation, preventing IFN-β gene transcription. Recombinant EBOVs with mutated VP35 dsRNA-binding domains are markedly attenuated in non-human primate models, confirming VP35 as an essential virulence determinant.
5 · VP24 blocks STAT1 nuclear import — IFN signalling shut down
VP24 competes with phosphorylated STAT1 for binding to karyopherin-α1, -α5, and -α6 — the nuclear import adaptors required for ISG (interferon-stimulated gene) induction. By blocking STAT1 nuclear transport, VP24 prevents ISG induction even when IFN is produced by uninfected bystander cells. VP35 + VP24 together create a dual-layer IFN blockade uniquely potent: VP35 prevents IFN production, VP24 prevents IFN signalling — the host is effectively blind to the infection at the cytokine level.
6 · sGP antibody decoy and bystander lymphocyte apoptosis
A transcriptional editing event in the GP gene produces large quantities of soluble GP (sGP), a disulfide-linked homodimer antigenically similar to but distinct from the virion GP1,2 trimer. sGP is secreted at molar excess and absorbs anti-GP patient antibodies — an antibody sponge delaying humoral clearance. Separately, bystander lymphocyte apoptosis (via Fas/FasL and TRAIL pathways) depletes CD4+, CD8+, and NK cells without direct infection, creating profound immunosuppression alongside intense systemic inflammation — the paradox that defines fatal EVD.
Host Immune Response
Disease Spectrum — Ebola Virus Disease (EVD)
| Phase | Presentation | Severity | Mortality correlation |
|---|---|---|---|
| Incubation | 2–21 days (typically 4–10); asymptomatic; not infectious | None | — |
| Prodromal (Days 1–3) | Abrupt fever (≥38.6°C), severe headache, fatigue, myalgia — clinically indistinguishable from malaria or typhoid; contact history is the key epidemiological clue | Moderate | Viral load at day 3 predicts outcome |
| Gastrointestinal (Days 3–7) | Profuse watery diarrhoea (3–10 L/day), vomiting, abdominal pain — major source of dehydration; electrolyte derangements (hyponatraemia, hypokalaemia, metabolic acidosis) | Severe | GI fluid losses drive hypovolaemic shock |
| Peak viremia (Days 5–10) | Viral loads 10⁸–10¹⁰ copies/mL in fatal cases; DIC onset; petechiae, ecchymoses; splenic necrosis; markedly elevated AST/ALT (hepatocellular necrosis) | Critical | 10¹⁰ copies/mL → >80% CFR |
| Hemorrhagic (Days 7–12) | Overt bleeding (oozing IV sites, haematemesis, melaena, epistaxis) in ~50% of cases — NOT the dominant cause of death; most deaths are from shock + MOF | Critical | Hemorrhage = DIC complication |
| Recovery / Late complications | Survivors: fever defervescence, weeks of recovery; EBOV may persist in semen (>500 days post-clearance), CSF, aqueous humor — sexual transmission documented. Post-EVD syndrome: arthralgia, uveitis, hearing loss, neurological sequelae | Convalescent | ~40% of survivors have post-EVD syndrome |
Treatment & Prevention
| Inmazeb (FDA Oct 2020) | Triple mAb cocktail (atoltivimab + maftivimab + odesivimab); targets GP1 (two non-overlapping RBD epitopes) + GP2 fusion loop; single IV infusion. PALM RCT (DRC 2018–19): 28-day mortality ~34% vs ~49% in control; efficacy highest in low-viremia early-treated patients (<20% mortality). |
| Ebanga (FDA Dec 2020) | Single mAb (ansuvimab); targets GP1 receptor-binding domain; similar efficacy to Inmazeb in PALM trial; single IV dose. |
| Ervebo (FDA Dec 2019) | rVSV-ZEBOV-GP (Merck); live recombinant VSV with VSV-G replaced by EBOV GP; single dose; ring vaccination strategy (contacts + contacts-of-contacts ≤21 days post-exposure). >97% efficacy in Guinea Ebola Ça Suffit! trial (Henao-Restrepo 2017). WHO prequalified. Used in ongoing DRC outbreaks. |
| Zabdeno + Mvabea (EMA 2020) | Johnson & Johnson two-dose regimen: Ad26.ZEBOV prime (day 0) + MVA-BN-Filo boost (day 56); for broader population prophylaxis including HCWs; less stringent cold-chain requirements than Ervebo. |
| Supportive care | Cornerstone: aggressive IV/oral rehydration (matching GI losses 3–10 L/day); electrolyte correction; antiemetics; analgesics; management of secondary infections; DIC management (FFP, platelets). Barrier nursing in full PPE (BSL-3/4 level) mandatory for HCWs — PPE failures drove healthcare transmission in 2014–16. |
Connections
References
- Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–62. doi:10.1016/S0140-6736(10)60667-8 · PubMed 21084112
- Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease (Ebola Ça Suffit!). Lancet. 2017;389(10068):505–18. doi:10.1016/S0140-6736(16)32621-6 · PubMed 28017403
- Carette JE, Raaben M, Wong AC, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340–3. doi:10.1038/nature10348 · PubMed 21866103
- Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics (PALM). N Engl J Med. 2019;381(24):2293–303. doi:10.1056/NEJMoa1910993 · PubMed 31774950
- Geisbert TW, Hensley LE. Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions. Expert Rev Mol Med. 2004;6(20):1–24. doi:10.1017/S1462399404008300 · PubMed 15504257
- Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020.
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This entry covers EBOV biology, NPC1 entry, immune evasion, EVD clinical course, and approved therapies. Planned expansions: Sudan/Bundibugyo cross-protection data, VP35 dsRNA-binding structure, and Marburg virus comparison. Every entry follows the same schema: structured frontmatter, peer-reviewed citations, and cross-atlas links.