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

Influenza A virus (IAV) poses 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 ten immunosuppressants, explored the antiviral mechanisms of immunosuppressants and demonstrated the combination effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibited viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibited 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 at risk of influenza virus infection.