Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice

Aaruni Khanolkar; Stacey M Hartwig; Brayton A Haag; David K Meyerholz; John T Harty; Steven M Varga

doi:10.1128/JVI.01857-08

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Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice

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Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice

Aaruni Khanolkar, Stacey M Hartwig, Brayton A Haag, David K Meyerholz, John T Harty and Steven M Varga

Journal of virology, Vol.83(17), pp.8946-8956

09/2009

DOI: 10.1128/JVI.01857-08

PMCID: PMC2738158

PMID: 19553337

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Abstract

Severe acute respiratory syndrome (SARS) is characterized by substantial acute pulmonary inflammation with a high mortality rate. Despite the identification of SARS coronavirus (SARS-CoV) as the etiologic agent of SARS, a thorough understanding of the underlying disease pathogenesis has been hampered by the lack of a suitable animal model that recapitulates the human disease. Intranasal (i.n.) infection of A/J mice with the CoV mouse hepatitis virus strain 1 (MHV-1) induces an acute respiratory disease with a high lethality rate that shares several pathological similarities with SARS-CoV infection in humans. In this study, we examined virus replication and the character of pulmonary inflammation induced by MHV-1 infection in susceptible (A/J, C3H/HeJ, and BALB/c) and resistant (C57BL/6) strains of mice. Virus replication and distribution did not correlate with the relative susceptibilities of A/J, BALB/c, C3H/HeJ, and C57BL/6 mice. In order to further define the role of the host genetic background in influencing susceptibility to MHV-1-induced disease, we examined 14 different inbred mouse strains. BALB.B and BALB/c mice exhibited MHV-1-induced weight loss, whereas all other strains of H-2 b and H-2 d mice did not show any signs of disease following MHV-1 infection. H-2 k mice demonstrated moderate susceptibility, with C3H/HeJ mice exhibiting the most severe disease. C3H/HeJ mice harbor a natural mutation in the gene that encodes Toll-like receptor 4 (TLR4) that disrupts TLR4 signaling. C3H/HeJ mice exhibit enhanced morbidity and mortality following i.n. MHV-1 infection compared to wild-type C3H/HeN mice. Our results indicate that TLR4 plays an important role in respiratory CoV pathogenesis.

Pathogenesis and Immunity

Details

Title: Subtitle: Toll-Like Receptor 4 Deficiency Increases Disease and Mortality after Mouse Hepatitis Virus Type 1 Infection of Susceptible C3H Mice
Creators: Aaruni Khanolkar - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
Stacey M Hartwig - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
Brayton A Haag - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
David K Meyerholz - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
John T Harty - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
Steven M Varga - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
Resource Type: Journal article
Publication Details: Journal of virology, Vol.83(17), pp.8946-8956
DOI: 10.1128/JVI.01857-08
PMID: 19553337
PMCID: PMC2738158
NLM abbreviation: J Virol
ISSN: 0022-538X
eISSN: 1098-5514
Publisher: American Society for Microbiology (ASM)
Language: English
Date published: 09/2009
Academic Unit: Graduate College Admin and Gen; Microbiology and Immunology; Pathology
Record Identifier: 9984047611702771

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