Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome

Abstract

Human cytomegalovirus (HCMV) is a major cause of viral disease in the young and the immune-suppressed. At sites of infection, HCMV recruits the neutrophil, a cell with a key role in orchestrating the initial immune response. Herein, we report a profound survival response in human neutrophils exposed to the clinical HCMV isolate Merlin, but not evident with the attenuated strain AD169, through suppression of apoptosis. The initial survival event, which is independent of viral gene expression and involves activation of the ERK/MAPK and NF-κB pathways, is augmented by HCMV-stimulated release of a secretory cytokine profile that further prolongs neutrophil lifespan. As aberrant neutrophil survival contributes to tissue damage, we predict that this may be relevant to the immune pathology of HCMV, and the presence of this effect in clinical HCMV strains and its absence in attenuated strains implies a beneficial effect to the virus in pathogenesis and/or dissemination. In addition, we show that HCMV-exposed neutrophils release factors that enhance monocyte recruitment and drive monocyte differentiation to a HCMV-permissive phenotype in an IL-6-dependent manner, thus providing an ideal vehicle for viral dissemination. This study increases understanding of HCMV–neutrophil interactions, highlighting the potential role of neutrophil recruitment as a virulence mechanism to promote HCMV pathology in the host and influence the dissemination of HCMV infection. Targeting these mechanisms may lead to new antiviral strategies aimed at limiting host damage and inhibiting viral spread.

A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity

“…The HCMV induced secretome is, interestingly, very similar to the reported exosomal BC secretome [41,46]. The cancer cells promote M2 tissue macrophages to display an anti-inflammatory phenotype characterized by secretion of IL-6, arginase, and iNOS, and increase STAT3 signaling.…”

“…HCMV infection promotes a cellular secretome that influences its micro-environment by enhancing production of important immunosuppressive mediators [41] of much relevance in cancer biology. These include the membrane-bound T regulatory (Treg) cell-expressed transforming growth factor β (TGF-β) and IL-10, which directly inhibit NK cell and T cell effector functions [42,43].…”

There Is Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

“…PMNs are rarely infected directly with cell-free virus [ 83 ]. Therefore, it appears that PMN infection is completely dependent on cell-to-cell spread [ 45 , 50 ].…”

“…This implies that UL146 and UL147 may have additional functions besides chemotaxis [ 47 ]. After viral exposure, PMNs have an increased life span and express a pro-survival secretome [ 83 ]. Interestingly, PMNs exposed to cell-free virus release pro-inflammatory factors that induce monocyte recruitment and drive monocyte differentiation [ 83 ].…”

There's Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

“…The neutrophil is recruited to the primary infection site where it encounters cell free CMV. This interaction induces the PMN to secrete molecules that recruit other innate immune cell to the primary infection site [83]. These other immune cells are potentially better targets and will then be the primary viral dissemination vehicle.…”