Treatment of highly pathogenic avian influenza A/H5N1 virus infection with mesenchymal stromal cells-derived exosomes

Abstract

Introduction: Antivirals like oseltamivir have been used to treat influenza virus infection, yet unable to reduce the severe mortality rate of highly pathogenic avian influenza (HPAI) H5N1. We have previously used mesenchymal stromal cells (MSCs) to reduce lung edema and improve survival of HPAI H5N1 infected mice in vivo. The therapeutic effect of MSCs attributes to the extracellular vesicles secreted by MSCs containing growth factors and anti-inflammatory proteins. Exosomes are tiny extracellular vesicles containing mRNA, lipids and proteins which are released by host cells into the lung microenvironment upon stimulation. These exosomes require less storage facility and are more appealing therapy than MSCs therapy. We therefore propose to investigate the therapeutic effects of exosomes released by MSCs (MSC-exosomes) on lung edema of H5N1-infected primary human alveolar epithelial cells (AECs) in vitro through the modulation of host innate immune response by increasing alternatively activated M2 macrophages. Method: Exosomes extracted from umbilical cord-derived MSCs were co-cultured with human peripheral blood-derived macrophages to study the immunomodulatory responses and alveolar fluid clearance (AFC) of the H5N1-infected AECs using in vitro lung injury model. These exosome-educated macrophages will be also analyzed for the phenotypic changes of inflammatory M1 and anti-inflammatory M2 macrophages. Result: Both MSC-exosome and exosome-educated macrophages restored the impaired AFC and reduced the pro-inflammatory cytokine production of the H5N1-infected AECs. Exosome-educated macrophages were found to have activated into anti-inflammatory M2 phenotype with more increased anti-inflammatory cytokine expression when compared to macrophages without MSC-exosomes co-culture. Conclusion: These results suggested that MSC-exosomes can increase edema clearance after H5N1 virus infection by inducing phenotypic changes of host macrophages to promote anti-inflammatory effect. In conclusion, MSC-exosomes can be a novel alternative treatment for human infection of HPAI H5N1 virus.