University of Duisburg-Essen, Institute of Immunology, Medical Faculty, Essen, Germany.
Heinrich-Heine-University, Insitute of Molecular Medicine II, Düsseldorf, Germany.
Clin Exp Immunol. 2019 Jan;195(1):64-73. doi: 10.1111/cei.13241.
Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti-viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169 macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin-specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169 macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169 macrophages. Tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cell signaling (NF-κB) have been found to promote the survival of infected CD169 macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein-Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies.
病毒感染可能是致命的，因为病毒的直接细胞病变作用或诱导强烈的、不受控制的炎症反应。病毒和宿主内在特性强烈调节病毒感染的结果。最近，我们确定了在何种情况下淋巴组织内病毒的增强复制对疾病的结果是有益的。这种强制的病毒复制促进了抗病毒免疫激活，并且出人意料地加速了病毒的控制。在这篇综述中，我们总结了促进强制病毒复制的机制。在感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）和水疱性口炎病毒（VSV）等模型病毒后，抗原呈递细胞和 CD169 巨噬细胞表现出强制病毒复制。CD169 巨噬细胞中的内源性 I 型干扰素阻断物泛素特异性肽酶 18（Usp18）已被鉴定为一种促病毒基因，B 细胞激活因子（BAFF）和癌胚抗原相关细胞黏附分子 1（CEACAM1）也是如此。淋巴毒素（LT）强烈增强脾脏和淋巴结中的病毒复制。所有这些因素都调节脾脏结构，从而促进 CD169 巨噬细胞的发育。肿瘤坏死因子-α（TNF-α）和核因子 kappa-轻链增强子的 B 细胞激活信号（NF-κB）已被发现可促进感染的 CD169 巨噬细胞的存活，从而同样促进强制病毒复制。感染与自身免疫性疾病的关联从以下几个方面显而易见：（1）在慢性病毒感染期间描述的自身免疫现象；（2）自身免疫性疾病与病毒感染同时发生；（3）实验证据。1 型糖尿病发病期间涉及病毒感染的证据非常明显。有人认为 EBV 感染与系统性红斑狼疮的发病机制有关。总之，有几种机制可促进次级淋巴器官中的病毒复制。在人类中确定这些因素是未来研究的挑战。
