SARS-CoV-2 envelope protein regulates innate immune tolerance

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.

Graphical abstract

Highlights

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  SARS-CoV-2 envelope (E) protein activated innate immune cells through TLR2

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  E protein promoted a long-term tolerant immune state after initial activation

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  Monocytes in this tolerant state had reduced responsiveness to secondary stimuli

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  E protein priming reduced lung inflammation markers to LPS in neonatal mice

Abstract

Molecular biology; Immunity; Components of the immune system; Virology; Transcriptomics.