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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 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 • • • • • • 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