Murine cytomegalovirus m119-118 encodes a new viral Fc receptor antagonizing host Fc receptor activation

Abstract Cytomegaloviruses (CMVs) encode numerous immunomodulatory proteins to counteract innate and adaptive immunity. One class of immune evasion proteins is viral Fc receptors (vFcRs), which bind to the Fc region of IgG antibodies and interfere with antibody-mediated effector functions crucial for antiviral defense. Despite the established role of vFcRs in modulating antibody-mediated immunity, their contribution to viral pathogenesis in vivo remains incompletely understood. Although human CMV (HCMV) encodes four vFcRs, only a single vFcR, fcr-1 encoded by gene m138 , has been identified in murine CMV (MCMV). By comparing and cloning the genomes of MCMV strains v70, K181 + , and K181 Perth , we identified a frameshift mutation affecting the spliced m119-118 transcript in K181 Perth . This finding prompted us to investigate the function of the m119-118 gene. We show that it encodes a second MCMV vFcR, which we named fcr-2. It is structurally similar to its positional homolog in HCMV, UL119-118/gp68, and binds specifically to the Fc part of murine IgG. Deletion of both vFcRs genes from the MCMV genome resulted in substantially reduced Fc-binding to the surface of infected cells, indicating a complementary function of the vFcRs. Functional assays with viral deletion mutants further demonstrated that both proteins inhibit host Fc receptor activation in a cooperative fashion. Although an m119-118-deficient MCMV was only marginally attenuated in infected BALB/c mice, an m119-118 and m138 double mutant attained significantly lower organ titers than the m138-deficient mutant. These data suggest an important cooperative function of the two MCMV vFcRs for viral dissemination and pathogenesis in vivo. Author Summary Cytomegaloviruses (CMVs) establish lifelong infections by evading elimination by the host immune system. One strategy used to achieve this is the expression of proteins that bind antibodies and interfere with antibody-mediated immune responses. Although several antibody-binding proteins have been identified in human CMV, only one has been described in mouse cytomegalovirus (MCMV), m138/fcr-1. In this study, we identified a second antibody-binding protein encoded by gene m119-118 , which we name fcr-2. We show that this protein binds IgG antibodies and acts together with m138/fcr-1 to suppress activation of host antibody-binding receptors. In mice, deletion of m119-118 alone had only a minor effect on viral infection. In contrast, deletion of both genes caused substantially greater defects in replication and spread than viruses lacking either gene alone. These findings demonstrate that MCMV uses at least two cooperating antibody-binding proteins to weaken antibody-dependent immune defenses and promote infection in vivo.