Hanson L K, Slater J S, Karabekian Z, Virgin H W, Biron C A, Ruzek M C, van Rooijen N, Ciavarra R P, Stenberg R M, Campbell A E
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA.
J Virol. 1999 Jul;73(7):5970-80. doi: 10.1128/JVI.73.7.5970-5980.1999.
Blood monocytes or tissue macrophages play a pivotal role in the pathogenesis of murine cytomegalovirus (MCMV) infection, providing functions beneficial to both the virus and the host. In vitro and in vivo studies have indicated that differentiated macrophages support MCMV replication, are target cells for MCMV infection within tissues, and harbor latent MCMV DNA. However, this cell type presumably initiates early, antiviral immune responses as well. In addressing this paradoxical role of macrophages, we provide evidence that the proficiency of MCMV replication in macrophages positively correlates with virulence in vivo. An MCMV mutant from which the open reading frames M139, M140, and M141 had been deleted (RV10) was defective in its ability to replicate in macrophages in vitro and was highly attenuated for growth in vivo. However, depletion of splenic macrophages significantly enhanced, rather than deterred, replication of both wild-type (WT) virus and RV10 in the spleen. The ability of RV10 to replicate in intact or macrophage-depleted spleens was independent of cytokine production, as this mutant virus was a poor inducer of cytokines compared to WT virus in both intact organs and macrophage-depleted organs. Macrophages were, however, a major contributor to the production of tumor necrosis factor alpha and gamma interferon in response to WT virus infection. Thus, the data indicate that tissue macrophages serve a net protective role and may function as "filters" in protecting other highly permissive cell types from MCMV infection. The magnitude of virus replication in tissue macrophages may dictate the amount of virus accessible to the other cells. Concomitantly, infection of this cell type initiates the production of antiviral immune responses to guarantee efficient clearance of acute MCMV infection.
血液单核细胞或组织巨噬细胞在鼠巨细胞病毒（MCMV）感染的发病机制中起关键作用，对病毒和宿主均发挥有益功能。体外和体内研究表明，分化的巨噬细胞支持MCMV复制，是组织内MCMV感染的靶细胞，并携带潜伏的MCMV DNA。然而，这种细胞类型可能也会启动早期抗病毒免疫反应。为了解决巨噬细胞这一矛盾的作用，我们提供证据表明，MCMV在巨噬细胞中的复制能力与体内毒力呈正相关。一个缺失开放阅读框M139、M140和M141的MCMV突变体（RV10）在体外巨噬细胞中的复制能力存在缺陷，并且在体内生长时高度减毒。然而，脾巨噬细胞的耗竭显著增强而非抑制了野生型（WT）病毒和RV10在脾脏中的复制。RV10在完整或巨噬细胞耗竭的脾脏中复制的能力与细胞因子的产生无关，因为与WT病毒相比，该突变病毒在完整器官和巨噬细胞耗竭的器官中都是细胞因子的弱诱导剂。然而，巨噬细胞是响应WT病毒感染产生肿瘤坏死因子α和γ干扰素的主要贡献者。因此，数据表明组织巨噬细胞发挥着净保护作用，并且可能作为“过滤器”保护其他高度易感细胞类型免受MCMV感染。组织巨噬细胞中病毒复制的程度可能决定其他细胞可接触到的病毒量。与此同时，这种细胞类型的感染启动抗病毒免疫反应的产生，以确保有效清除急性MCMV感染。
