1. Rodent-Borne Viral Diseases
Chapter 38

2. 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

3. Hantaviruses Family Bunyaviridae Genus Hantavirus Negative sense ssRNA
Tripartite segmented genome
S = nucleocapsid
M = Gn/Gc glycoproteins
L = RNA polymerase
Enveloped
70 nm particles

4. 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

5. 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)

6. 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

7. U. S. Distribution of Hantavirus Cases

8. Colorado Hantavirus Cases
67 cases, 25 fatal, through 2009
Nonfatal
Fatal
County

9. New World Hantaviruses

10. Hantavirus Rodent Reservoirs
Sigmodontinae
Arvicolinae
Murinae
Hantaan (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)

11. Cytokines in HCPS
Mori et al., 1999

12. The Role of Cytokines in Pulmonary Hantavirus Infections
Interleukin-1β
Interleukin-2
Interleukin-4
Interferon-γ
Tumor necrosis factor
Lymphotoxin
Pro-inflammatory
No direct viral cytopathology
Cytokine-mediated immunopathology

13. 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

14. Culture for Cytokine Gene Expression
T cells
APC
Viral Antigen
Extract RNA, compare gene-specific cDNA levels by real-time PCR (ratio)
2 days
For each rodent

15. Cytokine Profiles of Deer Mouse T Cells
Acutely-infected
None expressed IL-17
Deer Mouse
Fox-p3
Treg Phenotype
DM6001 (m) +
iTreg
DM6010 (m)
DM6012 (m)
DM6019 (f) -
Th3
Persistently-infected *
* p<0.05

16. Humans vs. Rodents Humans  Rodent hosts 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

17. Arenaviruses Family Arenaviridae Single-stranded ambisense RNA
90 nm diameter
Two gene segments
S - nucleocapsid, gp1, gp2
L - RNA polymerase
Enveloped

18. Arenaviruses *Category A and Select Agent Virus Distribution Disease
Lymphocytic choriomeningitis virus
global
mild to severe (meningitis)
Lassa virus*
West Africa
Severe, often fatal (Lassa fever)
Lujo virus*
South Africa
Severe, often fatal hemorrhagic fever
Junin virus*
Argentina
Severe, often fatal (Argentine hemorrhagic fever)
Machupo virus*
Bolivia
Severe, often fatal (Bolivian hemorrhagic fever)
Chapare virus*
Guanarito virus*
Venezuela
Severe, often fatal (Venezuelan hemorrhagic fever)
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

19. 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

20. 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