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 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 Rhodesia (present Zimbabwe)/South Africa UnknownNosocomial transmission Kisumu and Nairobi, Kenya Exposure in cave? Monkey contact? Nosocomial transmission Mombasa, KenyaExposure in cave?– Durba, DRC Exposure in gold mine Repeated primary introductions into humans Uíge, AngolaUnknown Nosocomial and community-based transmission Kamwenge, Uganda Exposure in gold mine? Presumed primary introductions in 2 cases, with subsequent person–person spread 425 Ebola Reston excluded

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 transmission Tandala, ZaireUnknown– Ogooué-Ivindo Province, Gabon Unknown Traditional healing practices, nosocomial and community-based transmission Kikwit, DRCUnknownNosocomial transmission Ogooué-Ivindo Province, Gabon Consumption of dead chimp Secondary spread to caregivers Ogooué-Ivindo Province, Gabon Unknown Exposure while hunting, traditional healing practices Johannesburg, South Africa Imported from Gabon by infected doctor Nosocomial transmission Ogooué-Ivindo Province, Gabon Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers, traditional healing practices Cuvette Ouest Region, ROC Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers Cuvette Ouest Region, ROC Hunting and consumption of nonhuman primates Exposure while hunting, secondary spread to caregivers Kasai Occidental Province, DRC Unknown Case History Ebola Reston excluded

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 transmission Nzara, SudanUnknownNosocomial transmission Gulu, UgandaUnknownNosocomial and community transmission Yambio, SudanUnknown 1741 Ivory Coast ebolavirus 1994Taï Forest, Côte d’Ivoire Necropsy of chimpanzee –10 Ebolavirus, un-known species 2007 Bundibugyo District, Uganda Unknown 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)

Jak/STAT Pathway