Toll-like receptor 4 deficiency increases disease and mortality after mouse hepatitis virus type 1 infection of susceptible C3H mice.
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.
Khanolkar
Aaruni
A
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Hartwig
Stacey M
SM
Haag
Brayton A
BA
Meyerholz
David K
DK
Harty
John T
JT
Varga
Steven M
SM
D000818:Animals; D001835:Body Weight; D018352:Coronavirus Infections / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D004198:Disease Susceptibility; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000276:immunology*; D012720:Severity of Illness Index; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000172:deficiency*
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4