| Mouse hepatitis virus, strain JHM (MHV-JHM), induces acute encephalitis and acute and chronic demyelinating diseases in susceptible rodents. The innate immune system recognizes virus pathogens and triggers antiviral immune responses to limit virus replication. In one model, JHM infection results in host death in as fast as 6--7 days with robust spread in the CNS. This may indicate that MHV-JHM compromises the innate immune response in the host, which subsequently impairs the adaptive immune response and facilitates virus replication.; Dendritic cells (DCs) initiate the adaptive immune response by processing and presenting viral antigens, as well as secreting cytokines and chemokines that regulate T cell development. Thus, infection and dysfunction of DCs potentially impair the antiviral immune responses. I found that MHV-JHM productively infected DCs with a preference for mature DCs. This preference is not due to differential expression of the virus receptor molecule. Infection with MHV-JHM results in decreased capacity of DCs to stimulate CD8 T cell proliferation in vitro. Although MHV-JHM positive DCs have not been detected in vivo, both CD8+ and CD11b+ splenic DCs were susceptible to the virus infection ex vivo.; As another essential component of the innate immune system, IFN-alpha/beta induces expression of a series of antiviral genes to establish an antiviral environment in the host. I showed that MHV-JHM neither triggered nuclear translocation of the essential IFN-beta transcription factors IRF-3 and NF-kappaB, nor blocked their activation and subsequent IFN-beta induction in response to poly I:C stimulation. Further, MHV infection did not actively inhibit IFN-beta production mediated by known host pattern-recognition receptors.; Many viral nonstructural proteins counteract the innate immune response and facilitate virus replication in the host. We found that the membrane-associated ORF6 protein, encoded by the human coronavirus associated with the Severe Acute Respiratory Syndrome (SARS-CoV), when inserted into the MHV-JHM genome, converted a sublethal infection to lethal encephalitis and enhanced virus growth in tissue culture cells. This indicates that the SARS-CoV protein is able to function in the context of a heterologous coronavirus infection. |
