Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome.
Human Cytomegalovirus Delays Neutrophil Apoptosis and Stimulates the Release of a Prosurvival Secretome.
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DOI：
10.3389/fimmu.2017.01185
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发表时间：
2017
影响因子：
7.3
通讯作者：
Chilvers ER
中科院分区：
文献类型：
--
作者：
Pocock JM;Storisteanu DML;Reeves MB;Juss JK;Wills MR;Cowburn AS;Chilvers ER
人巨细胞病毒（HCMV）是年轻人和免疫抑制者病毒性疾病的主要原因。在感染部位，HCMV招募中性粒细胞，这是一种在协调初始免疫反应中起关键作用的细胞。在此，我们报告了一个深刻的生存反应，在人类中性粒细胞暴露于临床HCMV分离梅林，但不明显的减毒株AD 169，通过抑制细胞凋亡。最初的存活事件不依赖于病毒基因表达，涉及ERK/MAPK和NF-κB通路的激活，通过HCMV刺激的分泌性细胞因子谱的释放而增强，进一步延长中性粒细胞寿命。由于异常的中性粒细胞存活有助于组织损伤，我们预测这可能与HCMV的免疫病理学有关，并且在临床HCMV毒株中存在这种效应而在减毒株中不存在这种效应意味着在发病机制和/或传播中对病毒具有有益作用。此外，我们发现，HCMV暴露的中性粒细胞释放的因子，增强单核细胞的招聘和驱动单核细胞分化的HCMV许可的表型在IL-6依赖的方式，从而提供了一个理想的车辆病毒传播。这项研究增加了对HCMV-中性粒细胞相互作用的理解，突出了中性粒细胞募集作为毒力机制的潜在作用，以促进宿主中的HCMV病理学并影响HCMV感染的传播。针对这些机制可能会导致新的抗病毒策略，旨在限制宿主损害和抑制病毒传播。
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.