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* Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland;
Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico;
Department of Immunology, Paul Ehrlich Institut, Langen, Germany; and
Department of Microbiology, Columbia University Medical Center, New York, NY 10032
The swift production of type I IFNs is one of the fundamental aspects of innate immune responses against viruses. Plasmacytoid dendritic cell-derived type I IFNs are of prime importance for the initial control of highly cytopathic viruses such as the mouse hepatitis virus (MHV). The aim of this study was to determine the major target cell populations of this first wave of type I IFNs. Generation of bone marrow-chimeric mice expressing the type I IFN receptor (IFNAR) on either hemopoietic or non-bone marrow-derived cells revealed that the early control of MHV depended mainly on IFNAR expression on hemopoietic cells. To establish which cell population responds most efficiently to type I IFNs, mice conditionally deficient for the IFNAR on different leukocyte subsets were infected with MHV. This genetic analysis revealed that IFNAR expression on LysM+ macrophages and CD11c+ dendritic cells was most important for the early containment of MHV within secondary lymphoid organs and to prevent lethal liver disease. This study identifies type I IFN-mediated cross-talk between plasmacytoid dendritic cells on one side and macrophages and conventional dendritic cells on the other, as an essential cellular pathway for the control of fatal cytopathic virus infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This project received financial support from the Swiss National Science Foundation, Deutsche Forschungsgemeinschaft, and the National Institutes of Health (Grant AI067804 to B.R.).
2 Address correspondence and reprint requests to Dr. Burkhard Ludewig, Research Department, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland. E-mail address: burkhard.ludewig{at}kssg.ch
3 Abbreviations used in this paper: MHV, mouse hepatitis virus; pDC, plasmacytoid dendritic cell; cDC, conventional dendritic cell; IFNAR, type I IFNR; ALT, alanine 2-oxoglutarate aminotransferase.
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