Human cytomegalovirus (CMV) is the most common infection encountered in transplantation and is an important cause of morbidity and mortality in both solid organ and bone marrow transplant recipients. In addition to causing tissue-invasive disease, a variety of sequelae termed “indirect effects” have been attributed to immune modulation by CMV in transplant recipients, including increased susceptibility to opportunistic infections and increased risk of mortality from invasive fungal disease. However, the mechanisms by which CMV modulates the innate immune system to mediate this “indirect effect” are not well understood. Because monocytes and monocyte-derived macrophages (MDM) have a critical role in host defense and are also particularly permissive to primary, latent and reactivated CMV infection, we infected these cells isolated from CMV naïve (IgG negative) subjects with GFP-tagged CMV (TB40/E). We then analyzed the ability of infected monocytes to clear fungal pathogens using imaging flow cytometry (Amnis) and unbiased transcriptomic profiling by RNASeq. We found that CMV-infected human monocytes and MDM do not effectively phagocytose C. albicans or C. neoformans, and this deficit is mediated by altered expression of genes involved in pathogen recognition, intracellular killing, inflammasome activation and reactive oxygen species production. Specifically, we identify scavenger receptors, which have been shown to mediate fungal clearance, as critical links between CMV viremia and diminished ability to phagocytose fungal pathogens. Taken together, our data define a novel pathway by which CMV modulates the innate immune response by regulating scavenger receptor expression on monocytes and MDM, thereby rendering the immunocompromised host more susceptible to opportunistic infections, even in the absence of additional immunosuppression.

CITATION INFORMATION: Sen P., Wilkie A. R., Fernandes R., Lane R. J., Hickman S. E., Means T. K., Rosenberg E. R., Coen D. M., Fishman J. A., El Khoury J. Defective Innate Immune Response to Opportunistic Pathogens in Cytomegalovirus-Infected Monocytes Am J Transplant. 2017;17 (suppl 3).

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