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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., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Increased inflammation caused by SARS-CoV-2 infection can lead to severe coronavirus disease 2019 (COVID-19) and long-term disease manifestations. The mechanisms of this variable long-term immune activation are poorly defined. One feature of this increased inflammation is elevated levels of proinflammatory cytokines and chemokines. Autoantibodies targeting immune factors such as cytokines, as well as the viral host cell receptor, angiotensin-converting enzyme 2 (ACE2), have been observed after SARS-CoV-2 infection. Autoantibodies to immune factors and ACE2 could interfere with normal immune regulation and lead to increased inflammation, severe COVID-19, and long-term complications., Methods: Here, we deeply profiled the features of ACE2, cytokine, and chemokine autoantibodies in samples from patients recovering from severe COVID-19. We measured the levels of immunoglobulin subclasses (IgG, IgA, IgM) in the peripheral blood against ACE2 and 23 cytokines and other immune molecules. We then utilized an ACE2 peptide microarray to map the linear epitopes targeted by ACE2 autoantibodies., Results: We demonstrate that ACE2 autoantibody levels are increased in individuals with severe COVID-19 compared with those with mild infection or no prior infection. We identify epitopes near the catalytic domain of ACE2 targeted by these antibodies. Levels of autoantibodies targeting ACE2 and other immune factors could serve as determinants of COVID-19 disease severity, and represent a natural immunoregulatory mechanism in response to viral infection., Conclusions: These results demonstrate that SARS-CoV-2 infection can increase autoantibody levels to ACE2 and other immune factors. The levels of these autoantibodies are associated with COVID-19 disease severity., (© 2024. The Author(s).)