School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
Child Health Research Center, University of Queensland, South Brisbane, Australia.
J Virol. 2019 Jan 17;93(3). doi: 10.1128/JVI.01378-18. Print 2019 Feb 1.
Cytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a nonessential fusion complex component of both human CMV (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract. , MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact, but penetration was delayed. In contrast, myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, the tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization. Human cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focused on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore, targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections.
巨细胞病毒（CMV）在多种细胞类型中引发全身性感染。改变趋向性的糖蛋白可能会指导其传播。糖蛋白 O（gO）是人类巨细胞病毒（HCMV）和鼠巨细胞病毒（MCMV）融合复合物的非必需组成部分。我们测试了它对 MCMV 从呼吸道传播的贡献。缺乏 gO 的 MCMV 难以感染成纤维细胞和上皮细胞。细胞结合完好，但穿透延迟。相比之下，髓样细胞感染得以保留，而在肺部，髓样细胞和 2 型肺泡上皮细胞是主要的病毒靶标，缺乏 gO 的 MCMV 表现出对髓样细胞感染的明显偏好。其对上皮细胞的感染不良与原发性病毒产量低和毒力降低有关。通过感染 CD11c 髓样细胞进行的系统性传播最初是完整的，但随后减弱，因为上皮细胞感染较少最终导致髓样细胞感染减少。因此，外周和系统性 MCMV 感染之间的紧密联系使 gO 依赖性感染在宿主定植中起着核心作用。人类巨细胞病毒是导致先天性疾病的主要原因。这反映了其全身性传播的能力。需要一种疫苗，但最佳的病毒靶标尚不清楚。人们的注意力集中在病毒包膜融合复合物上。它有 2 种形式，因此我们需要知道每种形式对宿主定植的贡献。一种包括病毒糖蛋白 O。我们使用具有等效融合复合物的鼠巨细胞病毒来确定粘膜感染后糖蛋白 O 的重要性。我们表明它驱动上皮细胞中的局部病毒复制。它不是感染建立系统性感染的髓样细胞所必需的，但作为次要效应，局部复制不良会减少系统性传播。因此，靶向人类巨细胞病毒的糖蛋白 O 有可能减少局部和系统性感染。
