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Study on the Pharmacological Effects of Organogermanium Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during Influenza a Virus Infection

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Title: Study on the Pharmacological Effects of Organogermanium Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during Influenza a Virus Infection
Other Titles: インフルエンザウイルス感染時におけるRIG-Iを介したウイルス認識およびウイルス複製に対する有機ゲルマニウム化合物THGPの薬理学的効果に関する研究
Authors: Baidya, Sunanda Browse this author
Issue Date: 24-Dec-2021
Publisher: Hokkaido University
Abstract: During microbial infections, microbes-associated molecular patterns (MAMPs) are mainly recognized by pattern recognition receptors (PRRs), including transmembrane-type Toll-like receptors (e.g., TLR3 and TLR9) and cytoplasmic sensors, such as RIG-I (retinoic acidinducible gene I), MDA5 (melanoma differentiation-associated protein 5) and cGAS (cyclic GMP-AMP synthetase) to trigger antiviral immune responses. In addition to the interactions, the recognition of viral nucleic acids by viral polymerase is a crucial event during viral replication. It has previously been reported that, a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP) shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. The results of this study demonstrated that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5′-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA or lipopolysaccharide, which are ligands for MDA5, cGAS and TLR-4 respectively. Consistently, treatment with THGP resulted in dose-dependent suppression of type I IFN induction upon infections with influenza virus (FluV) and vesicular stomatitis virus that are known to be mainly sensed by RIG-I but not EMCV, recognized by MDA5. Mechanistically, detailed molecular analyses displayed that, THGP directly binds to the 5′-triphosphate moiety of viral RNA and 3pRNA and competes with RIG-I-mediated recognition, resulting in decreased type I interferon production. Furthermore, it has been observed that, THGP can directly counteract replication of FluV but not EMCV, by inhibiting the interaction of viral polymerase with RNA genome. Moreover, THGP treatment restored the body weight loss and improved the survival rate of FluV-infected mice, whereas the treatment with THGP itself did not show any toxic effect on survival or the body-weight curves of uninfected mice. Finally, FluV nucleoprotein RNA levels were significantly reduced in the lung tissues of THGP-treated mice, as compared with untreated mice. These results suggest a possible therapeutic implication of THGP that shows direct antiviral action together with a suppressive activity of innate inflammation.
Conffering University: 北海道大学
Degree Report Number: 甲第14738号
Degree Level: 博士
Degree Discipline: 理学
Examination Committee Members: (主査) 教授 村上 洋太, 教授 髙岡 晃教, 特任教授 髙木 睦, 講師 佐藤 精一
Degree Affiliation: 総合化学院(総合化学専攻)
Type: theses (doctoral)
Appears in Collections:課程博士 (Doctorate by way of Advanced Course) > 総合化学院(Graduate School of Chemical Sciences and Engineering)
学位論文 (Theses) > 博士 (理学)

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