MCK2-mediated MCMV infection of macrophages and virus dissemination to the salivary gland depends on MHC class I molecules
Berislav Bošnjak,
Elisa Henze,
Yvonne Lueder,
Kim Thi Hoang Do,
Alaleh Rezalotfi,
Berislav Čuvalo,
Christiane Ritter,
Anja Schimrock,
Stefanie Willenzon,
Hristo Georgiev,
Lea Fritz,
Melanie Galla,
Karen Wagner,
Martin Messerle,
Reinhold Förster
Affiliations
Berislav Bošnjak
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany; Corresponding author
Elisa Henze
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Yvonne Lueder
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Kim Thi Hoang Do
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Alaleh Rezalotfi
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Berislav Čuvalo
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Christiane Ritter
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Anja Schimrock
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Stefanie Willenzon
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Hristo Georgiev
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Lea Fritz
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
Melanie Galla
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
Karen Wagner
Institute of Virology, Hannover Medical School, Hannover, Germany
Martin Messerle
Institute of Virology, Hannover Medical School, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany
Reinhold Förster
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany; German Centre for Infection Research (DZIF), Partner site Hannover, Hannover, Germany; Corresponding author
Summary: Murine cytomegalovirus (MCMV) infection of macrophages relies on MCMV-encoded chemokine 2 (MCK2), while infection of fibroblasts occurs independently of MCK2. Recently, MCMV infection of both cell types was found to be dependent on cell-expressed neuropilin 1. Using a CRISPR screen, we now identify that MCK2-dependent infection requires MHC class Ia/β-2-microglobulin (B2m) expression. Further analyses reveal that macrophages expressing MHC class Ia haplotypes H-2b and H-2d, but not H-2k, are susceptible to MCK2-dependent infection with MCMV. The importance of MHC class I expression for MCK2-dependent primary infection and viral dissemination is highlighted by experiments with B2m-deficient mice, which lack surface expression of MHC class I molecules. In those mice, intranasally administered MCK2-proficient MCMV mimics infection patterns of MCK2-deficient MCMV in wild-type mice: it does not infect alveolar macrophages and subsequently fails to disseminate into the salivary glands. Together, these data provide essential knowledge for understanding MCMV-induced pathogenesis, tissue targeting, and virus dissemination.
