ID: 237. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Borst, Katharina; Frenz, Theresa; Spanier, Julia; Tegtmeyer, Pia-Katharina; Chhatbar, Chintan; Namineni, Sukumar; Lienenklaus, Stefan; Köster, Mario; Heikenwälder, Mathias; Sutter, Gerd; Kalinke, Ulrich
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 108
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.240
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">Most viruses developed mechanisms that inhibit the induction or the function of type I interferon (IFN-I). Vaccinia virus (VACV), a large DNA-encoded poxvirus, encodes several IFN-I evasins, including the viral IFN-I receptor B18. Nevertheless, here we found that VACV infection still induced local IFN-I responses in secondary lymphoid organs, which are mainly sensed within the liver. VACV infected IFN-I receptor deficient (IFNAR−/−) mice developed fulminant disease, associated with high virus loads in organs such as liver and spleen, imbalanced cytokine responses within the blood, and eventually succumbed to infection. Elevated ALT/AST levels in the serum of VACV infected IFNAR−/− mice supported the hypothesis that IFNAR triggering of the liver played a major role in the antiviral response. Histological analysis of livers of VACV infected IFNAR−/− mice revealed a severe acute hepatitis, massive infiltration of immune cells, and acute tissue apoptosis in the absence of IFNAR-signaling. Interestingly, VACV infected mice with a hepatocyte selective IFNAR ablation (Alb-CreIFNARflox/flox) showed moderate hepatitis as observed in wild-type mice, whereas mice with a cell type-specific IFNAR deletion only in myeloid cells (LysM-CreIFNARflox/flox) showed enhanced hepatitis. Thus, local IFN-I responses sensed by myeloid cells prevented immunopathology within the liver, presumably due to the induction of myeloid derived suppressor cells (MDSC).</p> <p id="sp010">Collectively these results indicate that although the induction of serum IFN-I is sequestered, VACV infection induces local IFN-I responses that play a central role in modulating immune responses and thus in reducing immunopathology and hepatitis.</p> </sec> </abstract>