Herpesvirus entry mediator on radiation-resistant cell lineages promotes ocular herpes simplex virus 1 pathogenesis in an entry-independent manner.
Herpesvirus entry mediator on radiation-resistant cell lineages promotes ocular herpes simplex virus 1 pathogenesis in an entry-independent manner.
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DOI：
10.1128/mbio.01532-15
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发表时间：
2015-10-20
期刊：
影响因子：
6.4
通讯作者：
Longnecker R
中科院分区：
文献类型：
--
作者：
Edwards RG;Kopp SJ;Karaba AH;Wilcox DR;Longnecker R
眼部单纯疱疹病毒 1 (HSV-1) 感染会导致潜在致盲的免疫炎症综合征，即疱疹性基质角膜炎 (HSK)。疱疹病毒进入介质 (HVEM) 是一种广泛表达的肿瘤坏死因子 (TNF) 受体超家族成员，在免疫信号传导中发挥多种作用，通过与病毒糖蛋白 D (gD) 相互作用促进病毒进入，对 HSV-1 发病机制很重要。我们用 HSV-1 突变体对小鼠进行角膜感染，其中 HVEM 介导的进入被特异性消除，并发现 HVEM 进入突变体产生的临床疾病与对照病毒产生的临床疾病相当。 HVEM 介导的角膜细胞因子诱导，与 HVEM 依赖性角膜免疫细胞浸润水平的增加相关，也是与 gD 无关的。鉴于 HVEM 免疫信号的复杂性，我们使用造血嵌合小鼠来确定哪些 HVEM 表达细胞介导眼睛中的 HSV-1 发病机制。无论供体是野生型（WT）还是HVEM敲除（KO）菌株，HVEM KO受体都受到保护，免受眼部HSV-1的侵害，这表明抗辐射细胞类型（可能是角膜的常驻细胞）上的HVEM赋予与野生型类似的疾病易感性。总之，这些数据表明 HVEM 独立于进入而促进眼部发病机制，并表明该蛋白质特别对抗辐射细胞具有免疫调节作用。眼睛保持免疫特权，以保护特殊的眼组织（例如半透明角膜）免受导致视力下降的损伤。眼部单纯疱疹病毒 1 (HSV-1) 感染可破坏这种免疫特权，引发宿主反应，最终导致免疫炎症综合征疱疹基质性角膜炎 (HSK) 所见的大部分损害。我们之前的工作表明，HVEM（一种宿主 TNF 受体超家族成员，也充当病毒进入受体）是导致眼部 HSV-1 发病机制的关键成分，尽管其在此过程中的确切作用仍不清楚。我们假设 HVEM 通过免疫调节作用促进眼部炎症微环境，从而在眼部接种 HSV-1 后加剧疾病。研究协调这种异常免疫反应的机制有助于了解 HSK 的启动和维持，HSK 是发达国家感染性失明的主要原因之一。
Ocular herpes simplex virus 1 (HSV-1) infection leads to a potentially blinding immunoinflammatory syndrome, herpes stromal keratitis (HSK). Herpesvirus entry mediator (HVEM), a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling, facilitates viral entry through interactions with viral glycoprotein D (gD) and is important for HSV-1 pathogenesis. We subjected mice to corneal infection with an HSV-1 mutant in which HVEM-mediated entry was specifically abolished and found that the HVEM-entry mutant produced clinical disease comparable to that produced by the control virus. HVEM-mediated induction of corneal cytokines, which correlated with an HVEM-dependent increase in levels of corneal immune cell infiltrates, was also gD independent. Given the complexity of HVEM immune signaling, we used hematopoietic chimeric mice to determine which HVEM-expressing cells mediate HSV-1 pathogenesis in the eye. Regardless of whether the donor was a wild-type (WT) or HVEM knockout (KO) strain, HVEM KO recipients were protected from ocular HSV-1, suggesting that HVEM on radiation-resistant cell types, likely resident cells of the cornea, confers wild-type-like susceptibility to disease. Together, these data indicate that HVEM contributes to ocular pathogenesis independently of entry and point to an immunomodulatory role for this protein specifically on radiation-resistant cells. Immune privilege is maintained in the eye in order to protect specialized ocular tissues, such as the translucent cornea, from vision-reducing damage. Ocular herpes simplex virus 1 (HSV-1) infection can disrupt this immune privilege, provoking a host response that ultimately brings about the majority of the damage seen with the immunoinflammatory syndrome herpes stromal keratitis (HSK). Our previous work has shown that HVEM, a host TNF receptor superfamily member that also serves as a viral entry receptor, is a critical component contributing to ocular HSV-1 pathogenesis, although its precise role in this process remains unclear. We hypothesized that HVEM promotes an inflammatory microenvironment in the eye through immunomodulatory actions, enhancing disease after ocular inoculation of HSV-1. Investigating the mechanisms responsible for orchestrating this aberrant immune response shed light on the initiation and maintenance of HSK, one of the leading causes of infectious blindness in the developed world.