Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability

ABSTRACT

Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.

KEYWORDS:

• Influenza A virus
• immunosuppression
• Immunosuppressants
• antiviral agents

Abbreviation

IAV, Influenza A virus; MPA, Mycophenolic acid; 6-TG, 6-Thioguanine; M2, Matrix protein 2; M1, Matrix protein 1; HA, Hemagglutinin; NA, Neuraminidase; NS1, nonstructural-protein 1; ER, Endoplasmic Reticulum; UPR, Unfolded Protein Response; COVID-19, Coronavirus disease 2019; JAK, Janus kinase; m-TOR, Mammalian target of rapamycin; IMPDH, Inosine monophosphate dehydrogenase; GMP, Guanosine monophosphate; PTM, Post-translational modification.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Authorship

X.-M.Y. and X.-X.M. designed and supervised this study. X.W., F.-Y.P., X.-Y.Y., and X.-L.F. performed the experiments and data analysis. J.-Y.Z., K.D., and X.-X.N. provided scientific input and technical guidance and assistance to experiments. X.W. and F.-Y.P. wrote the manuscript, and Z.-R.M. proofed the article. All authors read and approved the final article.

Additional information

Funding

This work was supported by [the Central Universities Deriving from the Northwest Minzu University] under Grant [31920230001] and the [Gansu provincial Nature Science Funding] under Grant [20JR5A505].