Respiratory viruses induce the expression of type I and III IFNs in MSCs through RLR/IRF3 signaling pathways

Abstract

Mesenchymal stem cells (MSCs) comprise a primitive cell population and reside in various tissues and organs. These cells exhibit immunomodulatory activity and are effective in treating respiratory viral infections. The activation of type I and III interferons, which protect cells against viral infections, can be induced after pattern recognition receptors (PRRs) recognize viral nucleic acid species. Although certain viruses can upregulate IFN-β expression in MSCs, the underlying mechanisms and responsiveness to different IFNs are unclear. We found that foreskin-derived fibroblast-like stromal cells (FDSCs), a kind of functional MSC, were permissive to IAV PR8, HCoV-229E, and EV-D68. Infection by IAV PR8 and HCoV-229E increased the expression of IFN-β and IFN-λ species in FDSCs in an IRF-3-dependent manner. RIG-I was critical for detecting IAV PR8 in FDSCs, and IAV PR8 infection induced a significant increase in the expression of interferon signaling genes (ISGs). Interestingly, only IFN-β, but not IFN-λ species, could induce the expression of ISGs, a finding supported by our observation that only IFN-β induced STAT1 and STAT2 phosphorylation in FDSCs. We also proved that treatment with IFN-β suppressed the propagation of IAV PR8 and promoted the survival of virus-infected FDSCs. Respiratory viruses could infect FDSCs and induce the expression of IFN-β and IFN-λ1, but only IFN-β could protect FDSCs against viral infection.

Keywords: Foreskin-derived fibroblast-like stromal cells; Influenza A virus; Interferon regulatory factor; Interferons; Mesenchymal stem cells; RIG-I.