An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication.

Zihan Geng,Yaxin Wang,Yujing Shi,Yanyan Bao,Shanshan Guo,Mengping Chen,Lei Bao,Yingying Zhang,Lirun Zhou,Jing Sun,Rongmei Yao,Xiaolan Cui,Ronghua Zhao

doi:10.3389/fphar.2021.755796

Abstract

Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of several strains of the influenza virus. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the mechanism of geniposide on influenza A virus (IAV). The potential targets and signaling pathways of geniposide in the IAV infection were predicted using network pharmacology analysis. According to the result of network pharmacology analysis, we validated the calcium signaling pathway induced by IAV and investigated the effect of geniposide extracted from Gardenia jasminoides J.Ellis on this pathway. The primary Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways KEGG enrichment analysis indicated that geniposide has a multi-target and multi-pathway inhibitory effect against influenza, and one of the mechanisms involves calcium signaling pathway. In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.

Highlights

Influenza A virus (IAV) is common in all age group populations
The results suggested that the inhibition effect of geniposide on influenza A virus (IAV) replication might be related to the calcium signaling pathway
Current anti-influenza therapeutics and drugs in development are all directly targeted proteins encoded by the virus; for instance, oseltamivir inhibits NA, adamantanes block M2 ion channel, and the nucleoside analog favipiravir aims at RNAdependent RNA polymerase (RdRP) (Goldhill et al, 2018)

Summary

Introduction

Influenza A virus (IAV) is common in all age group populations. It has been regarded as a severe public health concern. It is one of the most common infectious diseases with a high incidence rate and high mortality rate (Tregoning et al, 2018). The most recent influenza pandemic caused by the H1N1 pdm influenza virus originated from swine spread rapidly to most countries and territories (Jain et al, 2009; Smith et al, 2009). Compared to seasonal influenza viruses, the H1N1 pdm influenza virus causes more severe disease and deaths among adults aged 18–64 years (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic Influenza, 2010; Chiu et al, 2011). Influenza has the potential for mortality, high mutation rates, and pandemic risk; it is crucial to learn more about the virulence and pathogenicity of influenza and identify the targets for the development of new drugs (Generous et al, 2014)

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