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

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.

The Organogermanium Compound 3-(Trihydroxygermyl) Propanoic Acid (THGP) Suppresses Inflammasome Activation Via Complexation with ATP

“…It has been also reported that Ge-132 suppresses influenza virus growth and reduces mouse mortality [ 34 ]. Most recently, it was revealed that THGP has dual effects in suppressing the growth of influenza virus A and the development of pneumonia by directly binding to the 5′-triphosphate RNA of influenza virus A [ 35 ]. SARS-CoV-2, unlike influenza virus, was not found to interact with THGP.…”

Physiological Activity of Trace Element Germanium Including Anticancer Properties

“…The comprehensive study of the various biological activities of Ge-132 [ 8 ], including those that were previously known [ 36 ], particularly its antitumor [ 78 , 79 , 80 , 81 , 82 , 83 , 84 ] and immunomodulating [ 43 , 52 , 54 , 85 ] activities, also continued. In addition, Ge-132 is proposed as a treatment for a number of diseases: haemorrhagic and ischemic stroke [ 86 , 87 ], viral infections [ 43 , 54 , 88 , 89 , 90 ] (including COVID-19 [ 43 ]), various inflammatory diseases, particularly mastitis [ 4 ]. Next, this is suggested in the treatment of diabetes mellitus to reduce insulin resistance [ 91 ], and as an antioxidant for various disorders caused by oxidative stress [ 53 , 54 , 92 , 93 , 94 ] as well as in dermatological practice to heal skin wounds and protect the skin from reactive oxygen species [ 95 , 96 ].…”

Physiological Activity of Trace Element Germanium Including Anticancer Properties

“…In addition, Ge-132 is proposed as a treatment of a number of diseases: haemorrhagic and ischemic stroke [91,92], viral infections [43,54,[93][94][95] (including COVID-19 [43]), various inflammatory diseases, in particular mastitis [4]. Next, it is suggested in the treatment of diabetes mellitus to reduce insulin resistance [96], and as an antioxidant for various disorders caused by oxidative stress [53,54,[97][98][99] as well as in dermatological practice to heal skin wounds and protect the skin from reactive oxygen species [100,101].…”