Luganini Anna, Terlizzi Maria E, Gribaudo Giorgio
Laboratory of Microbiology and Virology, Department of Life Sciences and Systems Biology, University of Turin Turin, Italy.
Front Microbiol. 2016 May 13;7:715. doi: 10.3389/fmicb.2016.00715. eCollection 2016.
Following primary infection in humans, the human cytomegalovirus (HCMV) persists in a latent state throughout the host's lifetime despite a strong and efficient immune response. If the host experiences some form of immune dysregulation, such as immunosuppression or immunodeficiency, HCMV reactivates, thereby emerging from latency. Thus, in the absence of effective functional immune responses, as occurs in immunocompromised or immunoimmature individuals, both HCMV primary infections and reactivations from latency can cause significant morbidity and mortality. However, even in immunocompetent hosts, HCMV represents a relevant risk factor for the development of several chronic inflammatory diseases and certain forms of neoplasia. HCMV infection may shift between the lytic and latent state, regulated by a delicate and intricate balance between virus-mediated immunomodulation and host immune defenses. Indeed, HCMV is a master in manipulating innate and adaptive host defense pathways, and a large portion of its genome is devoted to encoding immunomodulatory proteins; such proteins may thus represent important virulence determinants. However, the pathogenesis of HCMV-related diseases is strengthened by the activities of bioactive molecules, of both viral and cellular origin, that are secreted from infected cells and collectively named as the secretome. Here, we review the state of knowledge on the composition and functions of HCMV-derived secretomes. In lytic infections of fibroblasts and different types of endothelial cells, the majority of HCMV-induced secreted proteins act in a paracrine fashion to stimulate the generation of an inflammatory microenvironment around infected cells; this may lead to vascular inflammation and angiogenesis that, in turn, foster HCMV replication and its dissemination through host tissues. Conversely, the HCMV secretome derived from latently infected hematopoietic progenitor cells induces an immunosuppressive extracellular environment that interferes with immune recognition and elimination of latently infected cells, thereby promoting viral persistence. Characterization of the composition and biological activities of HCMV secretomes from different types of infected cells will lay the foundation for future advances in our knowledge about the pathogenesis HCMV diseases and may provide targets for the development of novel antiviral intervention strategies.
在人类初次感染后，尽管宿主具有强大且有效的免疫反应，人巨细胞病毒（HCMV）仍会在宿主一生中处于潜伏状态。如果宿主经历某种形式的免疫失调，如免疫抑制或免疫缺陷，HCMV就会重新激活，从而从潜伏状态中显现出来。因此，在缺乏有效的功能性免疫反应的情况下，就像在免疫受损或免疫未成熟个体中发生的那样，HCMV初次感染和潜伏状态的重新激活都可能导致显著的发病率和死亡率。然而，即使在免疫功能正常的宿主中，HCMV也是几种慢性炎症性疾病和某些形式肿瘤发生发展的相关危险因素。HCMV感染可能在裂解状态和潜伏状态之间转换，这由病毒介导的免疫调节和宿主免疫防御之间微妙而复杂的平衡所调控。事实上，HCMV是操纵宿主固有和适应性防御途径的高手，其基因组的很大一部分致力于编码免疫调节蛋白；因此，这类蛋白可能代表重要的毒力决定因素。然而，HCMV相关疾病的发病机制因生物活性分子的作用而增强，这些分子既有病毒来源也有细胞来源，它们从感染细胞中分泌出来，统称为分泌组。在此，我们综述了关于HCMV来源分泌组的组成和功能的知识现状。在成纤维细胞和不同类型内皮细胞的裂解感染中，大多数HCMV诱导分泌的蛋白以旁分泌方式发挥作用，刺激感染细胞周围炎症微环境的形成；这可能导致血管炎症和血管生成，进而促进HCMV复制及其在宿主组织中的传播。相反，来自潜伏感染造血祖细胞的HCMV分泌组诱导一种免疫抑制性细胞外环境，干扰对潜伏感染细胞的免疫识别和清除，从而促进病毒持续存在。对来自不同类型感染细胞的HCMV分泌组的组成和生物学活性进行表征，将为我们未来深入了解HCMV疾病发病机制奠定基础，并可能为开发新型抗病毒干预策略提供靶点。
