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

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)

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

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)

Cytokines in HCPS Mori et al., 1999

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

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 cells APC Viral Antigen Extract RNA, compare gene-specific cDNA levels by real-time PCR (ratio) 2 days For each rodent

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

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

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

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

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