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Filoviruses. Chapter 38. Filoviruses. Filamentous RNA viruses Africa, Philippines Two genera Ebolavirus Marburgvirus (Africa only) Cause hemorrhagic fevers with high fatality rates (up to 90%) Infection appears to be by close contact with infected person Highly contagious
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Filoviruses • Chapter 38
Filoviruses • Filamentous RNA viruses • Africa, Philippines • Two genera • Ebolavirus • Marburgvirus (Africa only) • Cause hemorrhagic fevers with high fatality rates (up to 90%) • Infection appears to be by close contact with infected person • Highly contagious • First outbreak: 1967 (Marburg, Germany; Yugoslavia) • Vaccine company was processing primary kidney cells from African green monkeys (Cercopithecus aethiops) • Several workers developed a hemorrhagic fever • Several dozen infected by person-to-person transmission • Fewer than half died
Filoviruses • First Ebola outbreak: 1976 (Zaire, Sudan) • Hundreds infected • 70%-90% fatal • Sporadic outbreaks still occur in Africa • Three viruses • Ebola Zaire • Ebola Sudan • Ebola Reston (Virginia) • Reston, Virginia outbreak • Occurred in a monkey quarantine facility (JRH Biosciences) • Monkeys imported from Philippines began dying from HF • Samples sent to nearby military lab for ID • United States Army Medical Research Institute for infectious Diseases (USAMRIID) • EM showed shepherd’s crook particles • Facility was secured by Army • Nonpathogenic in humans
Filoviruses • Ecology • Suspected bat reservoirs • Unknown vector (if any) • Clinical spectrum • Vascular leakage • Viremia (high titer) • Bleeding from orifices • Disseminated intravascular coagulation • No known treatment • Vaccine • Experimental • Developed in 2005 • Protects guinea pigs from infection • Bioweapon • Soviets weaponized Marburg virus • Japanese cult Aum Shrinrkyo attempted to obtain an Ebolavirus
Bats are reservoirs? • Suspected Ebola virus hosts • Epomops franqueti (Franquet's epauleted bat) • Hypsignathus monstrosus (hammer-headed bat) • Myonycteris torquata (little collared fruit bat) • Suspectecte Marburg virus host • Rousettus aegyptiacus (Egyptian fruit bat)
Case History Ebola Reston excluded
Case History Ebola Reston excluded
Case History Ebola Reston excluded
Filoviruses • Negative-strand virus • 7 to 9 mRNAs • NP - nucleoprotein • polymerizes with vRNA into a spiral tube • VP35 - nonstructural • Type 1 interferon antagonist • Inhibits interferon response elements found in the promoters of many antiviral genes • Suppresses the pathway regulated by dsRNA-dependent protein kinase PKR • VP40 - matrix protein • GP - glycoprotein spike • lectin-specific • GP1 binding • GP2 fusion • VP30 - transcription factor • VP24 - virus assembly, STAT1 inhibitor • L - RNA-dependent RNA polymerase
Pathogenesis • Major clinical feature is inflammatory response resembling septic shock • Nonhuman primate models show initial replication in • Monocytes • Macrophages • Dendritic cells (blocking maturation to APC) • Some of these cells disseminate virus throughout the body • A systemic cytokine and chemokine inflammatory response occurs • Multisystem organ failure • Cell surface tissue factor triggers extrinsic coagulation pathway • Disseminated intravascular coagulation occurs • Endothelial cell infection appears late in disease • Two viral proteins suppress the type I interferon response • VP35 protein inhibits activation of interferon regulatory factor 3 • VP24 blocks STAT1 localization to the nucleus • Lymphocytes die by apoptosis (and not viral infection)
