Study on control of viral infection by manipulation of OAS1-RNaseL axis

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19440
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Morio Tomohiro 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: ウイルス感染症 / 自然免疫 / RNA分解 / タイプIインターフェロン / 種差

Outline of Final Research Achievements

he OAS1-RNaseL system plays an important role in viral defense mechanisms, but its activation also induces cellular injury. The OAS-RNaseL system is the primary antiviral function in rodents and bats, and it is not yet clear how the system works without minimal cellular damage in the species . Expression analysis of OAS isoforms in human alveolar basal cell epithelium-derived, monocyte-derived, fibroblast-derived, and bat-derived cell lines (TB1Lu) revealed that only OAS3 is expressed in TB1Lu. In addition, RNase L activity of OAS1, 2, and 3 in human-derived cell lines was examined by knocking-out each one of them. This revealed that the activity was almost abolished by OAS3 deletion. To analyze bat-derived monocytes and DCs, we attempted to establish iPS cells from TB1Lu. To directly elucidate the involvement of RNaseL in OAS1 gain-of-function mutations, we generated RNaseL KO iPS cells harboring the patient’s mutation.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

OASの発現調節、OAS1GOF変異の病態におけるRNaseLの関与、コウモリ免疫細胞系でのOASの働きを検討する基礎的なtoolを揃えたことは1つの成果である。本研究ではまた、ヒトの肺胞上皮細胞や単球系細胞で、OAS3がRNaseL活性制御で重要な役割を果たしている可能性を提示した。さらにコウモリの肺上皮細胞由来細胞でもOAS3が主として発現していたことから、今後抗ウイルス活性/RNaseL活性制御においてOAS3へのアプローチが必要になることを示唆する所見を得た。OASは各種RNAウイルスへの生体防御や、炎症反応に関与しており、今後さらに研究が広がる可能性がある。