Dual Effect of Organogermanium Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during Influenza a Virus Infection.

Sunanda Baidya,Yasuhiro Shimada,Seiichi Sato,Mizuki Kido,Kai Li,Hirotaka Nonaka,Koki Noguchi,Nozomi Sakurai,Satoshi Tadano,Taisho Yamada,Takashi Nakamura,Ayato Takada,Hirofumi Sawa,Yoko Nishimoto,Akinori Takaoka,Hiroko Miyamoto,Michihito Sasaki,Akiko Okubo ,Yasuko Orba ,K Ishikawa

doi:10.3390/v13091674

Sunanda Baidya, Yasuhiro Shimada + Show 18 more

Open Access

https://doi.org/10.3390/v13091674

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Abstract

The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. 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. Here, we show 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. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5′-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation.

Highlights

The innate immune system is the first line of host defense against invasion by a variety of microbes
We evaluated the effect of THGP treatment on viral genome replication upon infection with influenza virus (IAV), which produces RNA species carrying a 50 -triphosphate moiety that can be a ligand of RIG-I
THGP comparatively showed a dose-dependent suppressing effect on IAV replication in MAVS-deficient cells (Figure 4C), wherein the activation of the IFN-stimulated response element (ISRE)-driven luciferase gene was not observed (Figure S5G). These results suggest that THGP has direct antiviral activity, possibly through its interaction with the 50 -triphosphate of the IAV genome

Summary

Introduction

The innate immune system is the first line of host defense against invasion by a variety of microbes. The molecular sensor-mediated recognition of invading microbes is the first critical step that initiates the activation of this system. During viral infections, virus-associated molecular patterns, viral nucleic acids (RNA and DNA), are mainly targeted by pattern recognition receptors (PRRs), including transmembrane-type. Toll-like receptors (e.g., TLR3 and TLR9) and cytoplasmic sensors, such as RIG-I (retinoic acid-inducible gene I) and cGAS (cyclic GMP-AMP synthetase) [1,2,3,4]. In most cases, such viral sensors activate their downstream signaling to induce types I and III IFN genes, which confer antiviral states to the cell. Oligomerized RIG-I interacts with the adaptor protein MAVS/IPS-1 through the CARD domains, leading to the activation of the downstream gene induction programs such as IFNs and proinflammatory cytokines [1,4]

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