Intranasal mouse hepatitis virus type 1 (MHV-1) infection of mice induces lung pathology similar to that observed in severe acute respiratory syndrome (SARS) patients. However, the severity of MHV-1-induced pulmonary disease varies among mouse strains, and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS. Little is known about the host immune response to MHV-1 and how it might contribute to some of the pathological changes detected in infected mice. In this study we show that an intact type I interferon system and the adaptive immune responses are required for controlling MHV-1 replication and preventing morbidity and mortality in resistant C57BL/6J mice after infection. The NK cell response also helps minimize the severity of illness following MHV-1 infection of C57BL/6J mice. In A/J and C3H/HeJ mice, which are highly susceptible to MHV-1-induced disease, we demonstrate that both CD4 and CD8 T cells contribute to morbidity during primary infection, and memory responses can enhance morbidity and mortality during subsequent reexposure to MHV-1. However, morbidity in A/J and C3H/HeJ mice can be minimized by treating them with immune serum prior to MHV-1 infection. Overall, our findings highlight the role of the host immune response in contributing to the pathogenesis of coronavirus-induced respiratory disease.

No abstract

Severe acute respiratory syndrome (SARS) is characterized by substantial acute pulmonary inflammation and a high mortality rate. A novel human coronavirus, SARS-associated coronavirus (SARS-CoV), was identified as the etiologic agent of SARS. With the disappearance of SARS in the human population following the initial outbreak in 2003, limited information is available regarding the immunopathogenesis of SARS. Thus, an animal model that recapitulates the human disease would prove to be of great benefit, providing valuable insight into the pathology of the infection. Recent studies have demonstrated that intranasal infection of susceptible mouse strains with a related mouse coronavirus, mouse hepatitis strain 1 (MHV-1), produces acute respiratory disease and mortality that resembles human SARS cases. We find that intranasal infection with MHV-1 results in morbidity and some mortality in susceptible C3H/HeN (H-2k) mice. Interestingly, MHV-1 infection of C3H/HeJ mice, that harbor a natural mutation in their toll-like receptor 4 (TLR4) gene which renders TLR4 unable to properly signal, results in enhanced disease and increased mortality. In the absence of a functional TLR4 signal, we observe enhanced CD4 T cell responses, where as CD8 T cell responses remain unaltered. Our results indicate that TLR4 plays an important role in respiratory coronavirus pathogenesis.