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

Horizontal
Transmission
Urine
Feces
Throat swab
Blood (acute)

Spillover from
aerosolized
excreta

Hantaviruses probably originated

in shrews, moles or bats,
then jumped to rodents and diverged

Hemorrhagic Fever with Renal Syndrome (HFRS)

Nephritis

Eurasia

Hantavirus Disease

Ancient China

WWI

WW2

Korean War

(Pre-1993)

Virus isolation 1976 (Hantaan virus)

100,000 to 200,000 cases each year (5% mortality)

Hantavirus Cardiopulmonary
Syndrome
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

U. S. Distribution of Hantavirus Cases

Colorado Hantavirus Cases

67 cases, 25 fatal, through 2009
Nonfatal
Fatal
County

New World Hantaviruses

New York

Sin Nombre

Peromyscus leucopus

Peromyscus maniculatus

Prospect Hill
Microtus pennsylvanicus

Muleshoe
Sigmodon hispidus

Bloodland Lake
Microtus ochrogaster

Isla Vista

Bayou

Microtus californicus

Oryzomys palustris

Black Creek Canal

El Moro Canyon

Sigmodon hispidus

Reithrodontomys megalotis

Rio Segundo
Reithrodontomys mexicanus

Calabazo

Juquitiba

Zygodontomys brevicauda

Choclo

Ca o Delgadito
Sigmodon alstoni

Oligoryzomys fulvescens

Rio Mamore
Oligoryzomys microtis

Orn
Oligoryzomys longicaudatus

Bermejo
Oligoryzomys chacoensis

Andes
Oligoryzomys longicaudatus

Unknown Host Laguna Negra

Calomys laucha

Maciel
Necromys benefactus

Hu39694
Unknown Host

Lechiguanas
Oligoryzomys flavescens

Pergamino
Akodon azarae
CDC Website

Hantavirus Rodent
Reservoirs

Hantaan (Apodemus agrarius; East Asia)

Seoul (Rattus rattus; East Asia)

Murinae

Thailand (Bandicotta indica; Thailand)

Dobrava (Apodemus flavicollis; Slovenia)

Puumala (Clethrionomys galreolus; Northern Euope)

Tula (Microtus arvalis; Czech/Slovakia)

Arvicolinae
Prospect Hill (Microtus pennsylvanicus; MD-USA)
Black Creek Canal (Sigmodon hispidus; FL-USA)
Bayou (Oryzomys palustris; SE-USA)Sigmodontinae
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

The Role of Cytokines in

Pulmonary Hantavirus Infections

Interleukin-1
Interleukin-2
Interleukin-4
Interferon-
Tumor necrosis
factor
Lymphotoxin

Pro-inflammatory
No direct viral cytopathology
Cytokine-mediated immunopathology

Proliferation of Deer Mouse T Cells to

SNV
Acute Infection
KLH-specific T cells
(uninfected deer mice)

SNV N-Ag-specific T cells

(infected deer mice)

Persistent Infection
KLH-specific T cells
(uninfected deer mice)

SNV N-Ag-specific T cells

(infected deer mice)

Culture for Cytokine Gene Expression

T cells
APC

T cells
APC
Viral Antigen
2 days

For each rodent

Extract RNA, compare

gene-specific cDNA
levels by real-time PCR
(ratio)

Cytokine Profiles of Deer Mouse T

Cells
Acutely-infected

None expressed IL-17

Deer Mouse Fox-p3

Persistently-infected
*

* p<0.05

Treg Phenotype

DM6001 (m)

iTreg

DM6010 (m)

iTreg

DM6012 (m)

iTreg

DM6019 (f)

Th3

Humans vs. Rodents

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.)

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 Africa

Severe, often fatal (Lassa fever)

Lujo virus*

South Africa

Junin virus*

Argentina

Machupo virus*

Bolivia

Chapare virus*

Bolivia

Guanarito virus*

Venezuela

Tacaribe virus

Caribbean, Florida

Mild febrile illness

Pichinde virus

Colombia

None known

Whitewater arroyo virus

Western United States

Hemorrhagic fever, sometimes

fatal

*Category A and Select Agent

Severe, often fatal hemorrhagic

fever
Severe, often fatal (Argentine
hemorrhagic fever)
Severe, often fatal (Bolivian
hemorrhagic fever)
Severe, often fatal (Bolivian
hemorrhagic fever)
Severe, often fatal (Venezuelan
hemorrhagic fever)

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