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