The 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.
Heather L Menden, Sherry M Mabry, Aparna Venkatraman, Sheng Xia, Donald B DeFranco, Wei Yu, Venkatesh Sampath
Author Information
Heather L Menden: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States.
Sherry M Mabry: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States.
Aparna Venkatraman: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States.
Sheng Xia: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States.
Donald B DeFranco: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
Wei Yu: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States.
Venkatesh Sampath: Division of Neonatology, Department of Pediatrics, Children's Mercy, Kansas City, Missouri, United States. ORCID
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 [interleukin 6 (), tumor necrosis factor (), and interleukin 1 beta ()] and canonical proinflammatory 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 transforming growth factor beta (TGFβ) signaling was repressed in , but not mice. A single dose of intraperitoneal E protein injection induced chronic alveolar remodeling as evidenced by a decrease in radial alveolar counts and increase in mean linear intercepts. Ciclesonide, a synthetic glucocorticoid, inhibited E protein-induced proinflammatory TLR signaling and ALI. In vitro, E protein-mediated inflammation and cell death were TLR2-dependent in human primary neonatal lung endothelial cells and were rescued by ciclesonide. This study provides insight into the pathogenesis of ALI and alveolar remodeling with SARS-CoV-2 viremia in children, whereas revealing the efficacy of steroids. We reveal that the envelope protein of SARS-CoV-2 mediates acute lung injury (ALI) and alveolar remodeling through Toll-like receptor activation, which is rescued by the glucocorticoid, ciclesonide.
