Myeloid Infection Links Epithelial and B Cell Tropisms of Murid Herpesvirus-4
Myeloid Infection Links Epithelial and B Cell Tropisms of Murid Herpesvirus-4
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DOI：
10.1371/journal.ppat.1002935
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发表时间：
2012-09-01
期刊：
影响因子：
6.7
通讯作者：
Stevenson, Philip G.
中科院分区：
文献类型：
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作者：
Frederico, Bruno;Milho, Ricardo;Stevenson, Philip G.
γ-疱疹病毒持续存在于淋巴细胞中，并通过促进淋巴细胞增殖而引起疾病。因此，淋巴细胞感染是一个关键的致病事件。 Murid Herpesvirus-4 (MuHV-4) 是一种鼻病毒，与相关的卡波西肉瘤相关疱疹病毒一样，它在体内持续存在于 B 细胞中，但在体外很难感染它们。在这里，我们使用 MuHV-4 来了解病毒颗粒趋向性如何设定淋巴细胞定植的路径。体内具有高度传染性的病毒粒子表现出对 B 细胞感染的严重结合后阻断。因此，宿主进入是上皮感染，B细胞感染是次要事件。无细胞病毒颗粒对巨噬细胞的感染也很差，但当病毒颗粒结合改善或巨噬细胞与感染的成纤维细胞共培养时，巨噬细胞感染明显改善。相同条件下B细胞感染仍然较差；只有当病毒颗粒来自巨噬细胞时，这种情况才会有所改善。这反映了更好的细胞渗透并与病毒粒子融合复合物中的抗原变化相关。观察到巨噬细胞接触急性感染的上皮细胞，基于cre/lox的病毒标记显示几乎所有从淋巴组织中回收的病毒都通过了lysM(+)和CD11c(+)骨髓细胞。因此，MuHV-4 在 3 个不同的阶段到达 B 细胞：进入病毒粒子，感染上皮细胞；然后感染传递至骨髓细胞；糖蛋白的变化导致 B 细胞感染。这些数据确定了鼻病毒感染的新复杂性以及潜在的新干预脆弱性。
Gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. Lymphocyte infection is therefore a key pathogenetic event. Murid Herpesvirus-4 (MuHV-4) is a rhadinovirus that like the related Kaposi's Sarcoma-associated Herpesvirus persists in B cells in vivo yet infects them poorly in vitro. Here we used MuHV-4 to understand how virion tropism sets the path to lymphocyte colonization. Virions that were highly infectious in vivo showed a severe post-binding block to B cell infection. Host entry was accordingly an epithelial infection and B cell infection a secondary event. Macrophage infection by cell-free virions was also poor, but improved markedly when virion binding improved or when macrophages were co-cultured with infected fibroblasts. Under the same conditions B cell infection remained poor; it improved only when virions came from macrophages. This reflected better cell penetration and correlated with antigenic changes in the virion fusion complex. Macrophages were seen to contact acutely infected epithelial cells, and cre/lox-based virus tagging showed that almost all the virus recovered from lymphoid tissue had passed through lysM(+) and CD11c(+) myeloid cells. Thus MuHV-4 reached B cells in 3 distinct stages: incoming virions infected epithelial cells; infection then passed to myeloid cells; glycoprotein changes then allowed B cell infection. These data identify new complexity in rhadinovirus infection and potentially also new vulnerability to intervention.