SARS-CoV-2 E protein induces Toll like receptor 2-mediated neonatal lung injury in a model of COVID-19 viremia that is rescued by the glucocorticoid ciclesonide.

Abstract

SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll like receptor (TLR) - mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines (Il6, Tnfα, and Il1β) and canonical pro-inflammatory TLR signaling. Systemic E protein induced endothelial immune activation, immune cell influx, and TGFβ signaling and lung matrix remodeling inhibited alveolarization in the developing lung. E protein-mediated ALI and TGFβ signaling was repressed in Tlr2-/-, but not Tlr4-/- mice. A single does of E protein induced chronic alveolar remodeling as evidenced by decreased radial alveolar counts and mean linear intercepts. Ciclesonide, a synthetic glucocorticoid, inhibited E protein-induced pro-inflammatory TLR signaling and ALI. In vitro, E protein mediated inflammation and cell death was TLR2-dependent in human primary neonatal lung endothelial cells, and was rescued by ciclesonide. This study provides insight into the pathogenesis of ALI and alveolar remodeling with SARS-CoV-2 viremia in children, while revealing the efficacy of steroids.