JVI Accepts, published online ahead of print on 10 October 2007

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J. Virol. doi:10.1128/JVI.01794-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Type 1 Interferons are Essential in Controlling Neurotropic Coronavirus Infection Irrespective of Functional CD8 T Cells

Derek D.C. Ireland, Stephen A. Stohlman, David R. Hinton, Roscoe Atkinson, and Cornelia C. Bergmann^*

Department of Neuroscience, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195 and Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033

^* To whom correspondence should be addressed. Email: bergmac{at}ccf.org.

Neurotropic coronavirus infection induces expression of both interferon (IFN)- RNA and protein in the infected rodent central nervous system (CNS). However, the relative contributions of type I IFN (IFN-I) to direct, cell type specific virus control, or CD8 T cell mediated effectors in the CNS are unclear. IFN-I receptor deficient (IFNAR^-/-) mice infected with a sub-lethal, demyelinating or a non pathogenic neurotropic virus variant both succumbed to infection within nine days. Compared to wild-type (wt) mice, replication was prominently increased in all glial cell types and spread to neurons, demonstrating expanded cell tropism. Furthermore, increased pathogenesis was associated with significantly enhanced accumulation of neutrophils, TNF-, IL-6, CCL2 and IFN- within the CNS. The absence of IFN-I signalling did not impair induction or recruitment of virus-specific CD8 T cells, the primary adaptive mediators of virus clearance in wt mice. Despite similar IFN- mediated MHC class II upregulation on microglia in infected IFNAR^-/- mice, class I expression was reduced compared to microglia in wt mice, suggesting a synergistic role of IFN-I and IFN- in optimizing class I antigen presentation. These data demonstrate a critical direct anti-viral role of IFN-I in controlling virus dissemination within the CNS, even in the presence of potent cellular immune responses. By limiting early viral replication and tropism, IFN-I controls the balance of viral replication and immune control in favor of CD8 T cell mediated protective functions.

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