Lawler Clara, Milho Ricardo, May Janet S, Stevenson Philip G
Sir Albert Sakzewski Virus Research Centre, School of Chemistry and Molecular Biosciences, Royal Children's Hospital and University of Queensland, Brisbane, Australia.
Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
PLoS Pathog. 2015 Mar 19;11(3):e1004761. doi: 10.1371/journal.ppat.1004761. eCollection 2015 Mar.
Rhadinoviruses establish chronic infections of clinical and economic importance. Several show respiratory transmission and cause lung pathologies. We used Murid Herpesvirus-4 (MuHV-4) to understand how rhadinovirus lung infection might work. A primary epithelial or B cell infection often is assumed. MuHV-4 targeted instead alveolar macrophages, and their depletion reduced markedly host entry. While host entry was efficient, alveolar macrophages lacked heparan - an important rhadinovirus binding target - and were infected poorly ex vivo. In situ analysis revealed that virions bound initially not to macrophages but to heparan⁺ type 1 alveolar epithelial cells (AECs). Although epithelial cell lines endocytose MuHV-4 readily in vitro, AECs did not. Rather bound virions were acquired by macrophages; epithelial infection occurred only later. Thus, host entry was co-operative - virion binding to epithelial cells licensed macrophage infection, and this in turn licensed AEC infection. An antibody block of epithelial cell binding failed to block host entry: opsonization provided merely another route to macrophages. By contrast an antibody block of membrane fusion was effective. Therefore co-operative infection extended viral tropism beyond the normal paradigm of a target cell infected readily in vitro; and macrophage involvement in host entry required neutralization to act down-stream of cell binding.
γ疱疹病毒会引发具有临床和经济重要性的慢性感染。有几种病毒通过呼吸道传播并导致肺部病变。我们利用鼠疱疹病毒4型（MuHV - 4）来了解γ疱疹病毒肺部感染的机制。通常认为初始感染部位是上皮细胞或B细胞。然而，MuHV - 4的靶细胞却是肺泡巨噬细胞，去除这些细胞会显著减少病毒进入宿主体内。虽然病毒进入宿主的效率较高，但肺泡巨噬细胞缺乏硫酸乙酰肝素——γ疱疹病毒一个重要的结合靶点——并且在体外很难被感染。原位分析显示，病毒粒子最初并非与巨噬细胞结合，而是与硫酸乙酰肝素阳性的1型肺泡上皮细胞（AECs）结合。虽然上皮细胞系在体外能轻易内吞MuHV - 4，但AECs却不能。相反，结合的病毒粒子会被巨噬细胞摄取；上皮细胞感染只会在之后发生。因此，病毒进入宿主是一个协同过程——病毒粒子与上皮细胞结合使得巨噬细胞能够被感染，而这反过来又使得AECs能够被感染。阻断上皮细胞结合的抗体并不能阻止病毒进入宿主：调理作用只是为病毒进入巨噬细胞提供了另一条途径。相比之下，阻断膜融合的抗体则是有效的。所以，协同感染使病毒嗜性超出了在体外能轻易感染靶细胞的正常模式；巨噬细胞参与病毒进入宿主需要中和作用在细胞结合的下游发挥作用。
