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MAVS 在大脑中对裂谷热病毒介导保护性免疫反应。

MAVS mediates a protective immune response in the brain to Rift Valley fever virus.

机构信息

Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California, United States of America.

School of Natural Sciences, University of California Merced, Merced, California, United States of America.

出版信息

PLoS Pathog. 2022 May 18;18(5):e1010231. doi: 10.1371/journal.ppat.1010231. eCollection 2022 May.

DOI:10.1371/journal.ppat.1010231
PMID:35584192
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9154093/
Abstract

Rift Valley fever virus (RVFV) is a highly pathogenic mosquito-borne virus capable of causing hepatitis, encephalitis, blindness, hemorrhagic syndrome, and death in humans and livestock. Upon aerosol infection with RVFV, the brain is a major site of viral replication and tissue damage, yet pathogenesis in this organ has been understudied. Here, we investigated the immune response in the brain of RVFV infected mice. In response to infection, microglia initiated robust transcriptional upregulation of antiviral immune genes, as well as increased levels of activation markers and cytokine secretion that is dependent on mitochondrial antiviral-signaling protein (MAVS) and independent of toll-like receptors 3 and 7. In vivo, Mavs-/- mice displayed enhanced susceptibility to RVFV as determined by increased brain viral burden and higher mortality. Single-cell RNA sequence analysis identified defects in type I interferon and interferon responsive gene expression within microglia in Mavs-/- mice, as well as dysregulated lymphocyte infiltration. The results of this study provide a crucial step towards understanding the precise molecular mechanisms by which RVFV infection is controlled in the brain and will help inform the development of vaccines and antiviral therapies that are effective in preventing encephalitis.

摘要

裂谷热病毒（RVFV）是一种高致病性的蚊媒病毒，能够在人类和牲畜中引起肝炎、脑炎、失明、出血综合征和死亡。气溶胶感染 RVFV 后，大脑是病毒复制和组织损伤的主要部位，但该器官的发病机制尚未得到充分研究。在这里，我们研究了 RVFV 感染小鼠大脑中的免疫反应。在感染过程中，小胶质细胞启动了抗病毒免疫基因的强烈转录上调，以及激活标志物水平的增加和细胞因子的分泌，这依赖于线粒体抗病毒信号蛋白（MAVS），并且独立于 Toll 样受体 3 和 7。在体内，Mavs-/- 小鼠表现出对 RVFV 的易感性增加，这表现为大脑病毒载量增加和死亡率升高。单细胞 RNA 序列分析在 Mavs-/- 小鼠的小胶质细胞中鉴定出 I 型干扰素和干扰素反应基因表达的缺陷，以及淋巴细胞浸润的失调。这项研究的结果为理解 RVFV 感染在大脑中受到控制的确切分子机制提供了重要的一步，并将有助于为预防脑炎的疫苗和抗病毒疗法的开发提供信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/99ea6392cd56/ppat.1010231.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/93ec1ee05dff/ppat.1010231.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/99ea6392cd56/ppat.1010231.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/a20dc64aadd2/ppat.1010231.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/1963bf1b5b6d/ppat.1010231.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c0/9154093/5ca2f4bf73e5/ppat.1010231.g003.jpg
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