Bridging the gap: Connecting the immunomodulatory effect of Human Cytomegalovirus’ viral protein vCXCL-1 on neutrophil-mediated regulation of monocytes 2702

Abstract Description Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality within the immunocompromised population. To cause dissemination and disease during reactivation or primary infection, HCMV has evolved a variety of immunomodulatory strategies to exploit and subvert the immune response. One of the HCMV gene products is UL146 (vCXCL-1), a viral homolog of host encoded chemokines such as CXCL-1and CXCL-8, which is highly polymorphic with the existence of 15 distinct isoforms across different strains. We previously demonstrated that these isoforms induce differing effector functions in neutrophils, but this does not account for systemic immunomodulation of innate immune cells during infection. Herein, we identify that classical monocytes express high levels of CXCR2, the cognate receptor for vCXCL-1. However, rather than exerting effects directly on monocytes, different isoforms of vCXCL-1 modulate the effector functions of monocytes indirectly by changing the cytokine/chemokines secreted by neutrophils. For example, we observe that supernatants from neutrophils stimulated with isoforms of vCXCL-1 differentially induce migration of monocytes, which may contribute to viral dissemination. Taken together, these data demonstrate how different isoforms of vCXCL-1 could use neutrophils to fine-tune monocytic responses in order to promote HCMV dissemination and disease. Funding Sources UTK Startup Funds Topic Categories Viral Immunology (VIR)