Abstract
Janus kinase (JAK) inhibitors have been developed as novel immunomodulatory drugs and primarily used for treating rheumatoid arthritis and other inflammatory diseases. Recent studies have suggested that this category of anti-inflammatory drugs could be potentially useful for the control of inflammation “storms” in respiratory virus infections. In addition to their role in regulating immune cell functions, JAK1 and JAK2 have been recently identified as crucial cellular factors involved in influenza A virus (IAV) replication and could be potentially targeted for antiviral therapy. Gingerenone A (Gin A) is a compound derived from ginger roots and a dual inhibitor of JAK2 and p70 S6 kinase (S6K1). Our present study aimed to determine the antiviral activity of Gin A on influenza A virus (IAV) and to understand its mechanisms of action. Here, we reported that Gin A suppressed the replication of three IAV subtypes (H1N1, H5N1, H9N2) in four cell lines. IAV replication was also inhibited by Ruxolitinib (Rux), a JAK inhibitor, but not by PF-4708671, an S6K1 inhibitor. JAK2 overexpression enhanced H5N1 virus replication and attenuated Gin A-mediated antiviral activity. In vivo experiments revealed that Gin A treatment suppressed IAV replication in the lungs of H5N1 virus-infected mice, alleviated their body weight loss, and prolonged their survival. Our study suggests that Gin A restricts IAV replication by inhibiting JAK2 activity; Gin A could be potentially useful for the control of influenza virus infections.
Highlights
Influenza is a highly contagious acute respiratory illness [1]
We first assessed the ability of Gingerenone A (Gin A) to inhibit influenza A virus (IAV) replication in 293T cells, a human embryonic kidney cell line
The 293T cells infected with H5N1 virus (0.01 multiplicity of infection (MOI)) were incubated in the absence or presence of the indicated concentrations of Gin A (10–50 μM) for 18, 24, or 36 h
Summary
Influenza is a highly contagious acute respiratory illness [1]. The disease is often presented as seasonal influenza epidemics and causes several hundred thousand deaths per year. Favipiravir, known as T-705, is an RNA polymerase inhibitor and has been approved for treating influenza virus infections in 2004 in Japan [7]. RNA polymerase, emerging IAV variants often become resistant to antiviral therapy, and vaccines lose their efficacy in protecting hosts from influenza virus infections [9]. The NS1 protein of the H1N1 virus activates the PI-3 kinase pathway and inhibits the virus-induced apoptotic signaling responses to increase virus replication [11] Targeting this pathway leads to the inhibition of IAV replication [12,13]. Recent studies using genome-wide screens to search for host factors as potential antiviral targets have led to the identification of a handful of molecules that play important roles in IAV replication [4]. JAK inhibitors are capable of restricting IAV replication and have the potential to be developed as novel antiviral drugs. Our study suggests that Gin A could be potentially developed as a novel antiviral agent for the control of IAV infections
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