リフトバレー熱ウイルスによる脳感染症から回復するために、薬物によって免疫反応をサポートできる可能性 Immune responses could be supported by drugs to help people recover from brain infections caused by Rift Valley fever virus
2022-11-10 ローレンスリバモア国立研究所(LLNL)
研究チームが調査した新興病原体はリフトバレー熱ウイルス(RVFV)と呼ばれ、これまでアフリカとアラビア半島での発生に限られていた病気である。
RVFVは、人や家畜に肝炎、脳炎、失明、出血性症候群、死亡などを引き起こす高病原性のウイルスである。牛、水牛、羊、山羊、ラクダなどの家畜に最もよく見られる。RVFVにエアロゾルで感染すると、ウイルスの複製が進み、脳の組織障害が発生する。
RVFVは、エアロゾル化によりバイオテロを引き起こす可能性があるとして、米国アレルギー感染症研究所によりカテゴリーAのバイオディフェンス病原体に分類されている。
マウスモデルを用いた研究で、チームはRVFVが人と哺乳類の脳にのみ存在するミクログリアと呼ばれる特別な免疫細胞に感染することを発見しました。
<関連情報>
- https://www.llnl.gov/news/lab-researchers-study-rift-valley-fever-virus
- https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010231
MAVSはリフトバレー熱ウイルスに対する脳の防御免疫反応を媒介する MAVS mediates a protective immune response in the brain to Rift Valley fever virus
Nicholas R. Hum,Feliza A. Bourguet,Aimy Sebastian,Doris Lam,Ashlee M. Phillips,Kristina R. Sanchez,Amy Rasley,Gabriela G. Loots,Dina R. Weilhammer
PLOS Pathogens Published: May 18, 2022
DOI:https://doi.org/10.1371/journal.ppat.1010231
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.
Author summary
Rift Valley fever virus causes severe disease in humans and livestock and in some cases can be fatal. There is concern about the use of Rift Valley fever virus as a bioweapon since it can be transmitted through the air, and there are no vaccines or antiviral treatments. Airborne transmission of the virus causes severe inflammation of the brain, yet little is known about the immune response against the virus in this organ. Here, we investigated the immune response in the brain to Rift Valley fever virus following intranasal infection. We determined that microglia, the resident immune cells of the brain, initiate a robust response to Rift Valley fever virus infection and identified a key immune pathway that is critical for the ability of microglia to respond to infection. When this immune pathway is rendered non-functional, mice have a dysregulated response to infection in the brain. This study provides insight into how the immune response can control Rift Valley fever virus infection of the brain.
