SARS-CoV-2 envelope protein regulates innate immune tolerance
Eric S. Geanes,
Rebecca McLennan,
Stephen H. Pierce,
Heather L. Menden,
Oishi Paul,
Venkatesh Sampath,
Todd Bradley
Affiliations
Eric S. Geanes
Genomic Medicine Center, Children’s Mercy Research Institute, Kansas City, MO, USA
Rebecca McLennan
Genomic Medicine Center, Children’s Mercy Research Institute, Kansas City, MO, USA
Stephen H. Pierce
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
Heather L. Menden
Division of Neonatology, Children’s Mercy Research Institute, Kansas City, MO, USA
Oishi Paul
Genomic Medicine Center, Children’s Mercy Research Institute, Kansas City, MO, USA
Venkatesh Sampath
Division of Neonatology, Children’s Mercy Research Institute, Kansas City, MO, USA; Department of Pediatrics, University of Missouri- Kansas City, Kansas City, MO, USA
Todd Bradley
Genomic Medicine Center, Children’s Mercy Research Institute, Kansas City, MO, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA; Department of Pediatrics, University of Missouri- Kansas City, Kansas City, MO, USA; Department of Pediatrics, University of Kansas Medical Center, Kansas City, MO, USA; Corresponding author
Summary: Severe COVID-19 often leads to secondary infections and sepsis that contribute to long hospital stays and mortality. However, our understanding of the precise immune mechanisms driving severe complications after SARS-CoV-2 infection remains incompletely understood. Here, we provide evidence that the SARS-CoV-2 envelope (E) protein initiates innate immune inflammation, via toll-like receptor 2 signaling, and establishes a sustained state of innate immune tolerance following initial activation. Monocytes in this tolerant state exhibit reduced responsiveness to secondary stimuli, releasing lower levels of cytokines and chemokines. Mice exposed to E protein before secondary lipopolysaccharide challenge show diminished pro-inflammatory cytokine expression in the lung, indicating that E protein drives this tolerant state in vivo. These findings highlight the potential of the SARS-CoV-2 E protein to induce innate immune tolerance, contributing to long-term immune dysfunction that could lead to susceptibility to subsequent infections, and uncovers therapeutic targets aimed at restoring immune function following SARS-CoV-2 infection.
