Chemokines and the regulation of innate and adaptive immunity following coronavirus infection of the central nervous system

We have used a model of viral-induced neurologic disease to better understand the mechanisms by which chemokines and chemokine receptors contribute to regulation of the immune response and leukocyte migration following viral infection of the CNS. Intracerebral infection of susceptible mice with mouse hepatitis virus (MHV), a positive-strand RNA virus, results in a dynamic expression pattern of chemokine and chemokine receptor genes that correlates with both host defense and disease development. To evaluate the functional contributions of CXCL10 to host defense and disease, we constructed two recombinant viral vectors. Infection of mice with either a CXCL10-expressing Adenovirus vector or a CXCL10-expressing MHV vector allowed us to further characterize the contributions of CXCL10 to host defense in the absence and presence, respectively, of an inflammatory response. Moreover, to further determine the precise contributions of CXCL10 during the early stage of MHV-induced disease in the absence of an adaptive immune response, RAG1−/− mice were infected with a recombinant MHV expressing CXCL10 and disease severity evaluated. In addition, the contributions of NK cells and IFN-γ to defense were also evaluated in this model. Furthermore, to evaluate the functional contributions of CCL3 to host defense and disease, mice lacking the ability to express CCL3 (CCL3−/−) were infected with MHV and disease severity determined. In both models, the immune response and pathology were measured by a series of techniques.; The results reported herein identify a novel role for the chemokine CXCL10 in the innate immune response through the recruitment and activation of NK cells. Moreover, our results identify for the first time a pivotal role for NK cell infiltration within the CNS and identify IFN-γ secretion as a primary effector mechanism required for the control of viral replication within the CNS. Our results also indicate that overexpression of CXCL10 during the early stage of MHV infection can amplify adaptive immune responses and protect mice from lethal doses of virus. Our results also identify a previously unappreciated role for CCL3 in the development of the adaptive immune response through contributing to the maturation and migration of myeloid dendritic cells into secondary lymphoid tissue. Taken together, the results presented here are important in that they identify novel roles for chemokines during the innate immune responses as well as the development of adaptive immunity to viral infection of the CNS.