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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 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 Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case CFR s (%) 1967 Marburg and Frankfurt, Germany; Imported monkeys from Uganda Dissection of monkeys to harvest organs, nosocomial transmission 32 22 1975 Rhodesia (present Zimbabwe)/South Africa Unknown Nosocomial transmission 3 33 1980 Kisumu and Nairobi, Kenya Exposure in cave? Monkey contact? Nosocomial transmission 2 50 1987 Mombasa, Kenya Exposure in cave? – 1 100 1998 Durba, DRC Exposure in gold mine Repeated primary introductions into humans 154 83 2004 Uíge, Angola Unknown Nosocomial and community-based transmission 252 90 2007 Kamwenge, Uganda Exposure in gold mine? Presumed primary introductions in 2 cases, with subsequent person–person spread 4 25 Marburgvirus Ebola Reston excluded Case History Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case CFR s (%) 1976 Yambuku, Zaire (present DRC) Unknown Nosocomial transmission 318 88 1977 Tandala, Zaire Unknown – 1 100 1994 Ogooué-Ivindo Province, Gabon Unknown Traditional healing practices, nosocomial and community-based transmission 49 59 1995 Kikwit, DRC Unknown Nosocomial transmission 315 81 1996 Ogooué-Ivindo Province, Gabon Consumption of dead chimp Secondary spread to caregivers 31 68 1996 Ogooué-Ivindo Province, Gabon Unknown Exposure while hunting, traditional healing practices 60 75 Nosocomial transmission 2 50 Zaire ebolavirus 1996 Johannesburg, South Imported from Gabon by Africa infected doctor 2001 Ogooué-Ivindo Province, Gabon Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers, traditional healing practices 124 78 2002 Cuvette Ouest Region, ROC Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers 143 89 2003 Cuvette Ouest Region, ROC Hunting and Exposure while hunting, secondary spread to consumption of caregivers nonhuman primates Ebola Reston excluded 35 83 Case History Virus and date of onset Epicenter(s) Source of primary infection Factors contributing to spread #Case CFR s (%) 1976 Maridi and Nzara, Sudan Unknown Nosocomial transmission 284 53 1979 Nzara, Sudan Unknown Nosocomial transmission 34 65 2000 Gulu, Uganda Unknown Nosocomial and community transmission 425 53 2004 Yambio, Sudan Unknown Unknown 17 41 Taï Forest, Côte d’Ivoire Necropsy of chimpanzee – 1 0 Bundibugyo District, Uganda Unknown Unknown 149 25 Sudan ebolavirus Ivory Coast ebolavirus 1994 Ebolavirus, un-known species 2007 Ebola Reston excluded Filoviruses Filoviruses Filoviruses 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) • • • • • • • • Jak/STAT Pathway