单纯疱疹病毒 1 型通过下调 GM130 抑制 TLR3 介导的固有免疫反应在小胶质细胞中免疫逃逸。

HSV-1 immune escapes in microglia by down-regulating GM130 to inhibit TLR3-mediated innate immune responses.

机构信息

Department of Neurology, Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, Hunan, China.

Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, Hunan, China.

出版信息

Virol J. 2024 Sep 16;21(1):219. doi: 10.1186/s12985-024-02492-x.

DOI:10.1186/s12985-024-02492-x

PMID:39285274

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11404012/

Abstract

BACKGROUND

To investigate the mechanism of Golgi matrix protein 130(GM130) regulating the antiviral immune response of TLR3 after herpes simplex virus type 1(HSV-1) infection of microglia cells. We explored the regulatory effects of berberine on the immune response mediated by GM130 and TLR3.

METHODS

An in vitro model of HSV-1 infection was established by infecting BV2 cells with HSV-1.

RESULTS

Compared to the uninfected group, the Golgi apparatus (GA) fragmentation and GM130 decreased after HSV-1 infection; TLR3 increased at 6 h and began to decrease at 12 h after HSV-1 infection; the secretion of interferon-beta(IFN-β), tumour necrosis factor alpha(TNF-α), and interleukin-6(IL-6) increased after infection. Knockdown of GM130 aggravated fragmentation of the GA and caused TLR3 to further decrease, and the virus titer also increased significantly. GM130 knockdown inhibits the increase in TLR3 and inflammatory factors induced by TLR3 agonists and increases the viral titer. Overexpression of GM130 alleviated fragmentation of the GA induced by HSV-1, partially restored the levels of TLR3, and reduced viral titers. GM130 overexpression reversed the reduction in TLR3 and inflammatory cytokine levels induced by TLR3 inhibitors. Therefore, the decrease in GM130 levels caused by HSV-1 infection leads to increased viral replication by inhibiting TLR3-mediated innate immunity. Berberine can protect the GA and reverse the downregulation of GM130, as well as the downregulation of TLR3 and its downstream factors after HSV-1 infection, reducing the virus titer.

CONCLUSIONS

In microglia, one mechanism of HSV-1 immune escape is disruption of the GM130/TLR3 pathway. Berberine protects the GA and enhances TLR3-mediated antiviral immune responses.

摘要

背景

为了研究高尔基基质蛋白 130（GM130）在单纯疱疹病毒 1（HSV-1）感染小胶质细胞后调节 TLR3 抗病毒免疫反应的机制，我们探讨了黄连素对 GM130 和 TLR3 介导的免疫反应的调节作用。

方法

用 HSV-1 感染 BV2 细胞建立 HSV-1 感染的体外模型。

结果

与未感染组相比，HSV-1 感染后高尔基器（GA）片段化和 GM130 减少；TLR3 在感染后 6 小时增加，12 小时开始减少；感染后干扰素-β（IFN-β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的分泌增加。敲低 GM130 加重 GA 片段化，导致 TLR3 进一步减少，病毒滴度也显著增加。GM130 敲低抑制 TLR3 激动剂诱导的 TLR3 和炎症因子的增加，并增加病毒滴度。GM130 的过表达缓解了 HSV-1 引起的 GA 片段化，部分恢复了 TLR3 的水平，并降低了病毒滴度。GM130 的过表达逆转了 TLR3 抑制剂诱导的 TLR3 和炎症细胞因子水平的降低。因此，HSV-1 感染导致 GM130 水平降低，通过抑制 TLR3 介导的固有免疫，导致病毒复制增加。黄连素可以保护 GA，并逆转 HSV-1 感染后 GM130、TLR3 及其下游因子的下调，降低病毒滴度。