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Monocytes Latently Infected with Human Cytomegalovirus Evade Neutrophil Killing.

ABSTRACT: One site of latency of human cytomegalovirus (HCMV) in vivo is in undifferentiated cells of the myeloid lineage. Although latently infected cells are known to evade host T cell responses by suppression of T cell effector functions, it is not known if they must also evade surveillance by other host immune cells. Here we show that cells latently infected with HCMV can, indeed, be killed by host neutrophils but only in a serum-dependent manner. Specifically, antibodies to the viral latency-associated US28 protein mediate neutrophil killing of latently infected cells. To address this mechanistically, a full proteomic screen was carried out on latently infected monocytes. This showed that latent infection downregulates the neutrophil chemoattractants S100A8/A9, thus suppressing neutrophil recruitment to latently infected cells. The ability of latently infected cells to inhibit neutrophil recruitment represents an immune evasion strategy of this persistent human pathogen, helping to prevent clearance of the latent viral reservoir.

SUBMITTER: Elder E

PROVIDER: S-EPMC6352302 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Project description:Human cytomegalovirus (HCMV) utilizes peripheral blood monocytes as a means to systemically disseminate throughout the host. Following viral entry, HCMV stimulates non-canonical Akt signaling leading to the activation of mTORC1 and the subsequent translation of select antiapoptotic proteins within infected monocytes. However, the full extent to which the HCMV-initiated Akt/mTORC1 signaling axis reshapes the monocyte translatome is unclear. We found HCMV entry alone was able to stimulate widescale changes to mRNA translation levels and that inhibition of mTOR, a component of mTORC1, dramatically attenuated HCMV-induced protein synthesis. Although monocytes treated with normal myeloid growth factors also exhibited increased levels of translation, mTOR inhibition had no effect, suggesting HCMV activation of mTOR stimulates the acquisition of a unique translatome within infected monocytes. Indeed, polyribosomal profiling of HCMV-infected monocytes identified distinct prosurvival transcripts that were preferentially loaded with ribosomes when compared to growth factor-treated cells. Sirtuin 1 (SIRT1), a deacetylase that exerts prosurvival effects through regulation of the PI3K/Akt pathway, was found to be highly enriched following HCMV infection in an mTOR-dependent manner. Importantly, SIRT1 inhibition led to the death of HCMV-infected monocytes while having minimal effect on uninfected cells. SIRT1 also supported a positive feedback loop to sustain Akt/mTORC1 signaling following viral entry. Taken together, HCMV profoundly reshapes mRNA translation in an mTOR-dependent manner to enhance the synthesis of select factors necessary for the survival of infected monocytes.IMPORTANCEHuman cytomegalovirus (HCMV) infection is a significant cause of morbidity and mortality among the immunonaïve and immunocompromised. Peripheral blood monocytes are a major cell type responsible for disseminating the virus from the initial site of infection. In order for monocytes to mediate viral spread within the host, HCMV must subvert the naturally short lifespan of these cells. In this study, we performed polysomal profiling analysis, which demonstrated HCMV to globally redirect mRNA translation toward the synthesis of cellular prosurvival factors within infected monocytes. Specifically, HCMV entry into monocytes induced the translation of cellular SIRT1 to generate an antiapoptotic state. Defining the precise mechanisms through which HCMV stimulates survival will provide insight into novel anti-HCMV drugs able to target infected monocytes.

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Monocytes Latently Infected with Human Cytomegalovirus Evade Neutrophil Killing.

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