1. Filoviruses Chapter 38

2. 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

3. Filoviruses

4. 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

5. 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

6. 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)

7. Case History Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case s CFR (%) Marburgvirus 1967 Marburg and Frankfurt, Germany; Imported monkeys from Uganda Dissection of monkeys to harvest organs, nosocomial transmission 3222 1975 Rhodesia (present Zimbabwe)/South Africa UnknownNosocomial transmission333 1980 Kisumu and Nairobi, Kenya Exposure in cave? Monkey contact? Nosocomial transmission250 1987Mombasa, KenyaExposure in cave?–1100 1998Durba, DRC Exposure in gold mine Repeated primary introductions into humans15483 2004Uíge, AngolaUnknown Nosocomial and community-based transmission 25290 2007Kamwenge, Uganda Exposure in gold mine? Presumed primary introductions in 2 cases, with subsequent person–person spread 425 Ebola Reston excluded

8. Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case s CFR (%) Zaire ebolavirus 1976 Yambuku, Zaire (present DRC) UnknownNosocomial transmission31888 1977Tandala, ZaireUnknown–1100 1994 Ogooué-Ivindo Province, Gabon Unknown Traditional healing practices, nosocomial and community-based transmission 4959 1995Kikwit, DRCUnknownNosocomial transmission31581 1996 Ogooué-Ivindo Province, Gabon Consumption of dead chimp Secondary spread to caregivers3168 1996 Ogooué-Ivindo Province, Gabon Unknown Exposure while hunting, traditional healing practices 6075 1996 Johannesburg, South Africa Imported from Gabon by infected doctor Nosocomial transmission250 2001 Ogooué-Ivindo Province, Gabon Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers, traditional healing practices 12478 2002 Cuvette Ouest Region, ROC Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers 14389 2003 Cuvette Ouest Region, ROC Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers 3583 2007 Kasai Occidental Province, DRC Unknown 26471 Case History Ebola Reston excluded

9. Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case s CFR (%) Sudan ebolavirus 1976 Maridi and Nzara, Sudan UnknownNosocomial transmission28453 1979Nzara, SudanUnknownNosocomial transmission3465 2000Gulu, UgandaUnknownNosocomial and community transmission42553 2004Yambio, SudanUnknown 1741 Ivory Coast ebolavirus 1994Taï Forest, Côte d’Ivoire Necropsy of chimpanzee –10 Ebolavirus, un-known species 2007 Bundibugyo District, Uganda Unknown 14925 Case History Ebola Reston excluded

10. Filoviruses

13. 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

14. 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)

15. Jak/STAT Pathway