Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, USA.
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
mBio. 2021 Aug 31;12(4):e0117621. doi: 10.1128/mBio.01176-21. Epub 2021 Jul 20.
We previously reported that herpes simplex virus 1 (HSV-1) ICP22 binds to CD80 and suppresses CD80 expression and . Similar to ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we asked whether, similar to ICP22-null virus, the absence of these costimulatory molecules will reduce HSV-1 infectivity. To test our hypothesis, CD28, CD28 CTLA4, PD-L1, and wild-type control BALB/c mice were ocularly infected with HSV-1 strain KOS. Levels of virus replication in the eye, corneal scarring (CS), latency, and reactivation in infected mice were determined. Expression of different genes in the trigeminal ganglia (TG) of latently infected mice was also determined by NanoString and quantitative reverse transcription-PCR (qRT-PCR). In the absence of costimulatory molecules, latency levels were higher than those in wild-type control mice, but despite higher latency, a significant number of TG from infected knockout mice did not reactivate. Reduced reactivation correlated with downregulation of 26 similar cellular genes that are associated with inflammatory signaling and innate immune responses. These results suggest that lower reactivation directly correlates with lower expression of interferon signaling. Thus, despite having different modes of actions, we identified a similar function for CD28, CTLA4, and PD-L1 in HSV-1 reactivation that is dependent on their interactions with CD80. Therefore, blocking these interactions could be a therapeutic target for HSV-1-induced reactivation. Costimulatory molecules play an important role in activation of T cell responses, and T cells contribute to HSV-1-induced eye disease in the host. Similar to HSV-1 ICP22, the cellular costimulatory molecules CD28, CTLA4, and PD-L1 also bind to CD80. In this study, we have shown that the absence of these costimulatory molecules significantly reduced HSV-1 reactivation. Therefore, inhibiting the binding of costimulatory molecules to CD80 could be used to reduce reactivation and, consequently, HSV-1-induced eye disease.
我们之前曾报道过单纯疱疹病毒 1（HSV-1）ICP22 与 CD80 结合并抑制 CD80 的表达。类似于 ICP22，细胞共刺激分子 CD28、CTLA4 和 PD-L1 也与 CD80 结合。在这项研究中，我们想知道，与 ICP22 缺失病毒类似，这些共刺激分子的缺失是否会降低 HSV-1 的感染力。为了验证我们的假设，我们用 HSV-1 株 KOS 对 CD28、CD28 CTLA4、PD-L1 缺失和野生型对照 BALB/c 小鼠进行了眼部感染。通过检测眼部病毒复制水平、角膜瘢痕（CS）、潜伏和感染小鼠的再激活，来确定病毒感染情况。还通过 NanoString 和定量逆转录-PCR（qRT-PCR）来确定潜伏感染小鼠三叉神经节（TG）中不同基因的表达情况。在缺乏共刺激分子的情况下，潜伏水平高于野生型对照小鼠，但尽管潜伏水平较高，从感染的敲除小鼠的 TG 中仍有大量未再激活。再激活减少与下调 26 个与炎症信号和先天免疫反应相关的相似细胞基因相关。这些结果表明，较低的再激活与干扰素信号的表达降低直接相关。因此，尽管作用机制不同，但我们发现 CD28、CTLA4 和 PD-L1 在 HSV-1 再激活中具有相似的功能，这依赖于它们与 CD80 的相互作用。因此，阻断这些相互作用可能成为治疗 HSV-1 诱导再激活的靶点。共刺激分子在 T 细胞反应的激活中起着重要作用，而 T 细胞在宿主的 HSV-1 诱导的眼部疾病中发挥作用。类似于 HSV-1 ICP22，细胞共刺激分子 CD28、CTLA4 和 PD-L1 也与 CD80 结合。在这项研究中，我们已经表明，这些共刺激分子的缺失显著降低了 HSV-1 的再激活。因此，抑制共刺激分子与 CD80 的结合可以用于减少再激活，从而减少 HSV-1 诱导的眼部疾病。
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