Innate triggering and antiviral effector functions of Activin A

Abstract

Background: First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by pattern recognition receptors, followed by activation of the type I IFN response and establishment of an antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. How these antiviral effects are mediated and triggered by viral infection has not been defined. Methods: Microarray and RNAseq data from hepatoma-derived cell lines stimulated with Activin A in vitro were interrogated both by pathway analysis and for evidence of IFN-stimulated gene induction. Liver tissue obtained from patients with chronic HCV were examined by real-time quantitative polymerase chain reaction (RT-qPCR) for evidence of Activin A induction. Activin expression by peripheral blood mononuclear cells exposed to nucleic acid analogues was quantified by RT-qCR, whereas induction dynamics in acute infection was investigated in in vitro Sendai virus infection and a murine influenza A. Results: Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant Activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, imurine influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating roles for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Conclusions: These data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions, with implications for the development of targeted antiviral therapies and revealing novel facets of Activin biology.