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Journal of Virology, September 2009, p. 8946-8956, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.01857-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Aaruni Khanolkar,1,{dagger} Stacey M. Hartwig,1,{dagger} Brayton A. Haag,3 David K. Meyerholz,2 John T. Harty,1,3 and Steven M. Varga1,3*

Department of Microbiology, University of Iowa, Iowa City, Iowa 52242,1 Department of Pathology, University of Iowa, Iowa City, Iowa 52242,2 Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa 522423

Received 3 September 2008/ Accepted 4 June 2009

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-2b and H-2d mice did not show any signs of disease following MHV-1 infection. H-2k 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.

* Corresponding author. Mailing address: 3-532 Bowen Science Building, 51 Newton Road, University of Iowa, Iowa City, IA 52242. Phone: (319) 335-7784. Fax: (319) 335-9006. E-mail: steven-varga{at}uiowa.edu

{triangledown} Published ahead of print on 24 June 2009.

{dagger} A.K. and S.M.H. contributed equally to this work.

Journal of Virology, September 2009, p. 8946-8956, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.01857-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Funk, C. J., Manzer, R., Miura, T. A., Groshong, S. D., Ito, Y., Travanty, E. A., Leete, J., Holmes, K. V., Mason, R. J. (2009). Rat respiratory coronavirus infection: replication in airway and alveolar epithelial cells and the innate immune response. J. Gen. Virol. 90: 2956-2964 [Abstract] [Full Text]  
  • Khanolkar, A., Hartwig, S. M., Haag, B. A., Meyerholz, D. K., Epping, L. L., Haring, J. S., Varga, S. M., Harty, J. T. (2009). Protective and Pathologic Roles of the Immune Response to Mouse Hepatitis Virus Type 1: Implications for Severe Acute Respiratory Syndrome. J. Virol. 83: 9258-9272 [Abstract] [Full Text]  


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