Transcript 12 Filoviruses

Filoviruses
Chapter 38
Filoviruses
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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
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Filoviruses
Filoviruses
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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
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Occurred in a monkey quarantine facility (JRH Biosciences)
Monkeys imported from Philippines began dying from HF
Samples sent to nearby military lab for ID
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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
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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
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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)
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Case History
Virus and
date of onset
Epicenter(s)
Source of primary
infection
Factors contributing to spread
#Case CFR
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(%)
1967
Marburg and Frankfurt,
Germany;
Imported monkeys
from Uganda
Dissection of monkeys to harvest organs,
nosocomial transmission
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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?
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1
100
1998
Durba, DRC
Exposure in gold
mine
Repeated primary introductions into humans
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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
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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
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1
100
1994
Ogooué-Ivindo
Province, Gabon
Unknown
Traditional healing practices, nosocomial and
community-based transmission
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59
1995
Kikwit, DRC
Unknown
Nosocomial transmission
315
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1996
Ogooué-Ivindo
Province, Gabon
Consumption of dead
chimp
Secondary spread to caregivers
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1996
Ogooué-Ivindo
Province, Gabon
Unknown
Exposure while hunting, traditional healing
practices
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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
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2002
Cuvette Ouest
Region, ROC
Hunting and
consumption of
nonhuman primates
Exposure while hunting, secondary spread to
caregivers
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2003
Cuvette Ouest
Region, ROC
Hunting and
Exposure while hunting, secondary spread to
consumption of
caregivers
nonhuman primates
Ebola Reston excluded
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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
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1979
Nzara, Sudan
Unknown
Nosocomial transmission
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2000
Gulu, Uganda
Unknown
Nosocomial and community transmission
425
53
2004
Yambio, Sudan
Unknown
Unknown
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Taï Forest, Côte d’Ivoire
Necropsy of
chimpanzee
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Bundibugyo District,
Uganda
Unknown
Unknown
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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
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Pathogenesis
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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)
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Jak/STAT
Pathway