Amniotic fluid derived extracellular vesicles as novel anti-inflammatory therapeutics against SARS-CoV-2 infection

Abstract

Abstract The ongoing Covid-19 pandemic caused by SARS-CoV-2 is associated with acute respiratory distress syndrome (ARDS) and fatal pneumonia. Excessive inflammation caused by SARS-CoV-2 is the key driver of ARDS and lethal disease. Despite strong evidence for the role of virus induced inflammation in severe COVID19, no effective anti-inflammatory drug is available to control robust inflammation. Although corticosteroids are in clinical use to suppress excessive inflammation, global immunosuppressive effects of these drugs have limited their clinical success. Moreover, cytotoxicity caused by several chemically derived drugs is a cause of concern. Therefore, there is an urgent need to identify biologically derived immunomodulators that suppress inflammation without affecting antiviral immunity. In this study, we evaluated human amniotic fluid derived extracellular vesicles (hAF-EVs) as a potential safe biologic for immunomodulation during Covid-19. Our results showed that hAF-EVs significantly reduced inflammatory cytokine production in TLR2/4/7 and CoV structural protein stimulated mouse macrophages, in-vitro. Importantly, we also found that intraperitoneal administration of hAF-EVs in mice infected with a mouse-adapted SARS-CoV-2 reduced morbidity and mortality. A detailed examination of infected lungs showed that the increased protection in hAF-EV-treated mice was associated with reduced myeloid cell accumulation and inflammatory cytokine production. Collectively, we identify a novel biologic that has potential to suppress excessive inflammation and promote survival following SARS-CoV-2 infection, highlighting the translational potential of hAF-EVs against Covid-19 and other viral lung infections. This study was supported in part by institutional research funds from Oklahoma State University—Stillwater and NIGMS 5P20GM103648-10.