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Rodent-Borne Viral Diseases

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.

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Rodent-Borne Viral Diseases

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  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. Spillover from aerosolized excreta Hantavirus Transmission Cycle Horizontal Transmission Urine Feces Throat swab Blood (acute) 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. 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) Prospect Hill (Microtus pennsylvanicus; MD-USA) Arvicolinae 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) Hantavirus Rodent Reservoirs

  11. Cytokines in HCPS Mori et al., 1999

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

  13. Acute Infection Persistent Infection KLH-specific T cells (uninfected deer mice) KLH-specific T cells (uninfected deer mice) SNV N-Ag-specific T cells (infected deer mice) SNV N-Ag-specific T cells (infected deer mice) Proliferation of Deer Mouse T Cells to SNV

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

  15. Acutely-infected Persistently-infected * * p<0.05 * * * * Cytokine Profiles of Deer Mouse T Cells None expressed IL-17

  16. Humans vs. Rodents 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 • 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.)

  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

  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

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