FilovirusesChapter 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 HistoryVirus and date of onset

Epicenter(s)Source of primary

infectionFactors contributing to spread

#Cases

CFR (%)

Marburgvirus

1967Marburg and

Frankfurt, Germany;Imported monkeys

from UgandaDissection of monkeys to harvest organs,

nosocomial transmission32 22

1975Rhodesia (present Zimbabwe)/South

AfricaUnknown Nosocomial transmission 3 33

1980Kisumu and Nairobi,

KenyaExposure in cave? Monkey contact?

Nosocomial transmission 2 50

1987 Mombasa, Kenya Exposure in cave? – 1 100

1998 Durba, DRCExposure in gold

mineRepeated primary introductions into

humans154 83

2004 Uíge, Angola UnknownNosocomial and community-based

transmission252 90

2007 Kamwenge, UgandaExposure in gold

mine?

Presumed primary introductions in 2 cases, with subsequent person–person

spread4 25

Ebola Reston excluded

Virus and date of onset

Epicenter(s)Source of primary

infectionFactors contributing to spread

#Cases

CFR (%)

Zaire ebolavirus

1976Yambuku, Zaire (present DRC)

Unknown Nosocomial transmission 318 88

1977 Tandala, Zaire Unknown – 1 100

1994Ogooué-Ivindo

Province, GabonUnknown

Traditional healing practices, nosocomial and community-based transmission

49 59

1995 Kikwit, DRC Unknown Nosocomial transmission 315 81

1996Ogooué-Ivindo

Province, GabonConsumption of dead

chimpSecondary spread to caregivers 31 68

1996Ogooué-Ivindo

Province, GabonUnknown

Exposure while hunting, traditional healing practices

60 75

1996Johannesburg, South Africa

Imported from Gabon by infected doctor

Nosocomial transmission 2 50

2001Ogooué-Ivindo

Province, Gabon

Hunting and consumption of

nonhuman primates

Exposure while hunting, secondary spread to caregivers, traditional healing

practices124 78

2002Cuvette Ouest Region, ROC

Hunting and consumption of

nonhuman primates

Exposure while hunting, secondary spread to caregivers

143 89

2003Cuvette Ouest Region, ROC

Hunting and consumption of

nonhuman primates

Exposure while hunting, secondary spread to caregivers

35 83

2007Kasai Occidental Province, DRC

Unknown Unknown 264 71

Case History

Ebola Reston excluded

Virus and date of onset

Epicenter(s)Source of primary

infectionFactors contributing to spread

#Cases

CFR (%)

Sudan ebolavirus

1976Maridi and Nzara,

SudanUnknown 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

Ivory Coast ebolavirus

1994Taï Forest, Côte

d’IvoireNecropsy of chimpanzee

– 1 0

Ebolavirus, un-known species

2007Bundibugyo District,

UgandaUnknown Unknown 149 25

Case History

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/STATPathway