rodent-borne viral diseases chapter 38. rodent-borne viral diseases rodents act as both vector and...
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Rodent-Borne Viral Diseases
Chapter 38
Rodent-Borne Viral Diseases
• Rodents act as both vector and reservoir
• Usually nonpathogenic in rodents
• Viruses often speciate with their rodent reservoirs
• Two principal groups
• Bunyaviruses
• Hantaviruses
• Arenaviruses
Hantaviruses
• Family Bunyaviridae
• Genus Hantavirus
• Negative sense ssRNA
• Tripartite segmented genome
• S = nucleocapsid
• M = Gn/Gc glycoproteins
• L = RNA polymerase
• Enveloped
• 70 nm particles
Hantavirus Transmission Cycle
Spillover fromaerosolized
excreta
HorizontalTransmission
UrineFeces
Throat swabBlood (acute)
Hantaviruses probably originatedin shrews, moles or bats,
then jumped to rodents and diverged
Hantavirus Disease(Pre-1993)
• Hemorrhagic Fever with Renal Syndrome (HFRS)
• Nephritis
• Eurasia
• Ancient China
• WWI
• WW2
• Korean War
• Virus isolation 1976 (Hantaan virus)
• 100,000 to 200,000 cases each year (5% mortality)
• First recognized in 1993 Four-Corners outbreak
• Specific to the Americas
• Acute febrile illness associated with headache, malaise and myalgia
• Progression to ARDS within 4-6 days characterized by thrombocytopenia, pulmonary edema, dyspnea and hypoxia
• 36% fatality rate due to cardiovascular shock
• Rapid, dramatic clinical progression
• Viral target: capillary endothelial cells
• Supportive care• Extracorporeal membrane oxygenation (ECMO)
• Relieves stress on heart
Hantavirus Cardiopulmonary Syndrome
U. S. Distribution of Hantavirus Cases
Colorado Hantavirus Cases67 cases, 25 fatal, through 2009
Nonfatal
Fatal
County
New World Hantaviruses
Sin NombreSin NombrePeromyscus maniculatus
Rio SegundoRio SegundoReithrodontomys mexicanusReithrodontomys mexicanus
El Moro CanyonEl Moro CanyonReithrodontomys megalotisReithrodontomys megalotis
AndesAndesOligoryzomys longicaudatusOligoryzomys longicaudatus
BayouBayouOryzomys palustrisOryzomys palustris
Black Creek CanalBlack Creek CanalSigmodon hispidusSigmodon hispidus
Rio MamoreRio MamoreOligoryzomys microtisOligoryzomys microtis
Laguna NegraLaguna NegraCalomys lauchaCalomys laucha
MuleshoeMuleshoeSigmodon hispidus
New YorkNew YorkPeromyscus leucopusPeromyscus leucopus
JuquitibaJuquitibaUnknown HostUnknown Host
MacielMacielNecromys benefactusNecromys benefactus
Hu39694Hu39694Unknown HostUnknown Host
LechiguanasLechiguanasOligoryzomys flavescensOligoryzomys flavescens
PergaminoPergaminoAkodon azaraeAkodon azarae
OrOránánOligoryzomys longicaudatusOligoryzomys longicaudatus
CCañaño Delgaditoo DelgaditoSigmodon alstoniSigmodon alstoni
Isla VistaIsla VistaMicrotus californicus
Bloodland LakeBloodland LakeMicrotus ochrogasterMicrotus ochrogaster
Prospect HillProspect HillMicrotus pennsylvanicusMicrotus pennsylvanicus
BermejoBermejoOligoryzomys chacoensisOligoryzomys chacoensis
CalabazoCalabazoZygodontomys brevicaudaZygodontomys brevicauda
ChocloChocloOligoryzomys fulvescensOligoryzomys fulvescens
CDC Website
Sigmodontinae
Arvicolinae
Murinae
Hantavirus Rodent ReservoirsHantaan (Apodemus agrarius; East Asia)
Seoul (Rattus rattus; East Asia)
Thailand (Bandicotta indica; Thailand)Dobrava (Apodemus flavicollis; Slovenia)
Puumala (Clethrionomys galreolus; Northern Euope)
Tula (Microtus arvalis; Czech/Slovakia)
Prospect Hill (Microtus pennsylvanicus; MD-USA)Black Creek Canal (Sigmodon hispidus; FL-USA)Bayou (Oryzomys palustris; SE-USA)
Hu39694 (unknown; Argentina)
Lechiguanas (Oligoryzomys flavescens; Argentina)Andes (Oligoryzomys longicaudatus; Argentina)
Laguna Negra (Calomys laucha; Paraguay/Bolivia)Sin Nombre (Peromyscus maniculatus; W-USA)
New York (Peromyscus leucopus; NE-USA)El Moro Canyon (Reithrodontomys megalotis; W-USA/N-Mexico)
Cytokines in HCPS
Mori et al., 1999
• Interleukin-1β• Interleukin-2
• Interleukin-4
• Interferon-γ• Tumor necrosis
factor
• Lymphotoxin
The Role of Cytokines inPulmonary Hantavirus Infections
Pro-inflammatory
No direct viral cytopathology
Cytokine-mediated immunopathology
Proliferation of Deer Mouse T Cells to SNV
KLH-specific T cells(uninfected deer mice)
SNV N-Ag-specific T cells(infected deer mice)
Acute Infection
KLH-specific T cells(uninfected deer mice)
SNV N-Ag-specific T cells(infected deer mice)
Persistent Infection
Culture for Cytokine Gene Expression
T cellsAPC
T cellsAPC
Viral Antigen
For each rodent
Extract RNA, compare gene-specific cDNA levels by real-time
PCR (ratio)
2 days
Persistently-infected
Cytokine Profiles of Deer Mouse T CellsAcutely-infected
* * * *
*
* p<0.05
Deer Mouse
Fox-p3Treg
PhenotypeDM6001
(m)+ iTreg
DM6010 (m)
+ iTreg
DM6012 (m)
+ iTreg
DM6019 (f) - Th3
None expressed IL-17
Humans Virus in lungs No viral CPE Pronounced pulmonary
inflammation Infected Cells Capillary endothelial Dendritic cells? Leukocyte infiltrates
T cells Macrophages
Inflammatory cytokines Respiratory insufficiency Neutralizing Ab 36% fatal (U. S.)
Humans vs. Rodents
Rodent hosts Virus in lungs No viral CPE No pulmonary inflammation Infected Cells Capillary endothelial No pulmonary mononuclear infiltrates Cytokines? TGFb (Treg cells) Cell phenotypes? No respiratory insufficiency Neutralizing Ab No death Chronic carrier
Arenaviruses
• Family Arenaviridae
• Single-stranded ambisense RNA
• 90 nm diameter
• Two gene segments
• S - nucleocapsid, gp1, gp2
• L - RNA polymerase
• Enveloped
Arenaviruses
Virus Distribution Disease
Lymphocytic choriomeningitis virus
global mild to severe (meningitis)
Lassa virus* West AfricaSevere, often fatal (Lassa
fever)
Lujo virus* South AfricaSevere, often fatal hemorrhagic fever
Junin virus* ArgentinaSevere, often fatal (Argentine
hemorrhagic fever)
Machupo virus* BoliviaSevere, often fatal (Bolivian
hemorrhagic fever)
Chapare virus* BoliviaSevere, often fatal (Bolivian
hemorrhagic fever)
Guanarito virus* VenezuelaSevere, often fatal
(Venezuelan hemorrhagic fever)
Tacaribe virus Caribbean, Florida Mild febrile illness
Pichinde virus Colombia None known
Whitewater arroyo virus Western United StatesHemorrhagic fever,
sometimes fatal
*Category A and Select Agent
Lassa Virus
• First diagnosed in late 1960s
• Two missionary nurses
• Lassa, Nigeria
• Reservoir is Mastomys spp. rodents
• Epidemiology
• About 200,000 cases per year
• About 5,000 fatalities per year
• Some evidence of person-to-person transmission
• Lassa Fever (hemorrhagic fever)
• Body aches, chest pain, vomiting, cough, fatigue
• Hypotension, pleural effusions, proteinuria, hearing loss in some survivors
• Higher fatality rate in pregnant women
• Fetal death in 95% of infections
Lassa Virus
• Animal model for Lassa fever: Pirital virus in hamsters
• Virus isolated from Alston's cotton rat (Sigmodon alstoni) in Guanarito, Venezuela (1994)
• BSL-3 agent
• Disease progression• All dead days 7-9
• Hemorrhages in lungs
• Pneumonia
• Pulmonary necrosis
• Splenic necrosis
• Lymphocyte depletion
• Mild myocarditis
• Hepatomegaly
• Hepatic necrosis
• Candidate vaccine available