Global transcriptional reprogramming by cytomegalovirus infection suppresses MHC class II antigen presentation while enhancing migration machinery in murine dendritic cells
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Dendritic cells (DCs) serve dual roles in cytomegalovirus infection: orchestrating antiviral immunity and acting as vehicles for viral dissemination. DC-dependent systemic spread of mouse cytomegalovirus (MCMV) is dependent on expression of a viral G protein-coupled receptor (GPCR) homolog, encoded by M33. We performed global transcriptional profiling of murine DCs infected with either wild-type mouse MCMV or a M33 mutant harbouring a single point mutation (R131Q; denoted M33NQY), which ablates constitutive G protein-dependent signalling. RNA-seq analysis revealed that MCMV induces substantial transcriptional reprogramming, with over 2,400 significantly altered genes affecting key immune and migration pathways. Wild-type MCMV infection resulted in 1,883 upregulated and 658 downregulated genes, while M33NQY infection showed comparable effects with 1,905 upregulated and 668 downregulated genes. Both viruses systematically downregulated the MHC class II antigen presentation machinery, with substantial suppression of H2 molecules, peptide-loading components ( H2-DMa/H2-DMb1 ), and the class II transactivator Ciita (log 2 FC > -6.4). Pathway analysis revealed coordinated disruption of B cell receptor signalling, leukocyte transendothelial migration, and antigen processing and presentation. A comparison between wild-type and M33NQY-infected DCs demonstrated that while both viruses similarly impair antigen presentation, M33 signalling specifically enhances the expression of genes involved in transendothelial migration, including Spp1 (osteopontin, log 2 FC = 0.65), cytoskeletal components ( Actg1, Actb ), adhesion molecules ( Icam1 ), and matrix interaction factors ( Tnc, Plau ). Network analysis identified critical hub genes, including B2m, Itgb1, Itgam , and Icam1 , as key regulatory nodes connecting antigen presentation and migration pathways. This provides molecular evidence for a sophisticated viral strategy that shields MCMV from immune detection while hijacking DC migratory machinery to facilitate dissemination, with M33 serving as a specific enhancer of migration-related pathways.
Impact Statement
This study provides the first comprehensive transcriptional profile of mouse cytomegalovirus (MCMV) infection in dendritic cells, revealing a sophisticated viral strategy that simultaneously suppresses antigen presentation while enhancing migration machinery. We identified that MCMV systematically downregulates the entire MHC class II pathway by targeting the master regulator Ciita , while the viral G protein-coupled receptor M33 specifically enhances genes involved in transendothelial migration, including Spp1 (osteopontin). Our network analysis identified critical hub genes connecting immune evasion and migration pathways, providing molecular evidence for how MCMV exploits dendritic cells as vehicles for dissemination while evading immune detection. These findings advance our understanding of betaherpesvirus pathogenesis and highlight potential therapeutic targets to limit viral spread.
