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Rodent-Borne Viral
Diseases
Chapter 38
Rodent-Borne Viral Diseases
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Rodents act as both vector and reservoir
Usually nonpathogenic in rodents
Viruses often speciate with their rodent reservoirs
Two principal groups
Bunyaviruses
Hantaviruses
Arenaviruses
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Hantaviruses
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Family Bunyaviridae
Genus Hantavirus
Negative sense ssRNA
Tripartite segmented genome
S = nucleocapsid
M = Gn/Gc glycoproteins
L = RNA polymerase
Enveloped
70 nm particles
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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
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Hemorrhagic Fever with Renal Syndrome (HFRS)
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Nephritis
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Eurasia
Hantavirus Disease
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Ancient China
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WWI
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WW2
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Korean War
(Pre-1993)
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Virus isolation 1976 (Hantaan virus)
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100,000 to 200,000 cases each year (5% mortality)
Hantavirus Cardiopulmonary
Syndrome
• First recognized in 1993 Four-Corners outbreak
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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
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Extracorporeal membrane oxygenation (ECMO)
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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
Or‡n
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
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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
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* p<0.05
Treg Phenotype
DM6001 (m)
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iTreg
DM6010 (m)
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iTreg
DM6012 (m)
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iTreg
DM6019 (f)
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Th3
Humans vs. Rodents
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Humans
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Virus in lungs
No viral CPE
Pronounced pulmonary
inflammation
Infected Cells
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 Capillary endothelial
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 Dendritic cells?
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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
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Family Arenaviridae
Single-stranded ambisense RNA
90 nm diameter
Two gene segments
S - nucleocapsid, gp1, gp2
L - RNA polymerase
Enveloped
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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
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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
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Lassa Virus
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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
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All dead days 7-9
Hemorrhages in lungs
Pneumonia
Pulmonary necrosis
Splenic necrosis
Lymphocyte depletion
Mild myocarditis
Hepatomegaly
Hepatic necrosis
Candidate vaccine available