Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns & Allen Research Institute, Los Angeles, California, United States.
Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3398-3406. doi: 10.1167/iovs.19-27701.
We previously have reported that ICP22, an immediate early gene of herpes simplex virus type 1 (HSV-1), binds to the CD80 promoter to suppress CD80 expression in antigen-presenting cells, leading to reduced T-cell function and protection. In contrast, overexpression of CD80 exacerbates corneal scarring (CS) in ocularly infected mice. In this study we tested the hypothesis that the absence of ICP22 could increase disease severity.
To test our hypothesis, BALB/c mice were ocularly infected after corneal scarification with a recombinant HSV-1 lacking the ICP22 gene with its parental wild-type (WT) virus (KOS) as a control. Virus replication in the eye, CS, angiogenesis, latency, and reactivation between ICP22 null virus and WT KOS were determined. In addition, expression of IL-2, IL-4, IFN-γ, IFN-α, granzyme A, granzyme B, and perforin by CD4 and CD8 T cells in corneas of infected mice on days 3, 5, 7, 10, 14, 21, and 28 postinfection were determined by flow cytometry.
We found similar levels of eye disease and angiogenesis in mice following corneal scarification and ocular infection with the ICP22 null virus or parental WT virus despite reduced virus replication in the eye and reduced latency and reactivation in mice ocularly infected with ICP22 null virus. The similar level of eye disease in ICP22 null virus- and WT virus-infected mice correlated with expression of various proinflammatory cytokines that infiltrated the eye after HSV-1 infection.
Our study identified a critical role for ICP22 in HSV-1 pathogenicity and suggests that HSV-1-associated CS is more dependent on host immune responses to infection than to virus replication in the eye. Thus, HSV-1 as means of survival uses ICP22 as a mechanism of immune escape that protects the host from increased pathology.
我们之前曾报道过，单纯疱疹病毒 1（HSV-1）的即刻早期基因 ICP22 与 CD80 启动子结合，抑制抗原呈递细胞中 CD80 的表达，从而降低 T 细胞功能并起到保护作用。相反，CD80 的过表达会加剧眼部感染小鼠的角膜瘢痕（CS）。在这项研究中，我们检验了 ICP22 缺失是否会增加疾病严重程度的假设。
为了验证我们的假设，用缺失 ICP22 基因的重组 HSV-1（其亲本野生型（WT）病毒 KOS 作为对照）对角膜划痕后的 BALB/c 小鼠进行眼部感染。检测眼内病毒复制、CS、血管生成、潜伏和再激活、ICP22 缺失病毒与 WT KOS 之间的差异。此外，通过流式细胞术检测感染后第 3、5、7、10、14、21 和 28 天，角膜中 CD4 和 CD8 T 细胞表达 IL-2、IL-4、IFN-γ、IFN-α、颗粒酶 A、颗粒酶 B 和穿孔素的情况。
尽管 ICP22 缺失病毒眼内病毒复制减少，潜伏和再激活减少，但在角膜划痕和眼部感染 ICP22 缺失病毒或亲本 WT 病毒的小鼠中，眼疾和血管生成的程度相似。ICP22 缺失病毒和 WT 病毒感染小鼠的眼部疾病程度相似，这与 HSV-1 感染后浸润眼睛的各种促炎细胞因子的表达有关。
我们的研究确定了 ICP22 在 HSV-1 致病性中的关键作用，并表明 HSV-1 相关的 CS 更依赖于宿主对感染的免疫反应，而不是眼内病毒复制。因此，HSV-1 作为生存手段，利用 ICP22 作为一种免疫逃避机制，保护宿主免受增加的病理损伤。
