Coronaviruses (CoVs) are RNA viruses that cause human respiratory infections. Zoonotic transmission of the SARS‐CoV‐2 virus caused the recent COVID‐19 pandemic, which led to over 2 million deaths worldwide. Elevated inflammatory responses and cytotoxicity in the lungs are associated with COVID‐19 severity in SARS‐CoV‐2‐infected individuals. Bats, which host pathogenic CoVs, operate dampened inflammatory responses and show tolerance to these viruses with mild clinical symptoms. Delineating the mechanisms governing these host‐specific inflammatory responses is essential to understand host–virus interactions determining the outcome of pathogenic CoV infections. Here, we describe the essential role of inflammasome activation in determining COVID‐19 severity in humans and innate immune tolerance in bats that host several pathogenic CoVs. We further discuss mechanisms leading to inflammasome activation in human SARS‐CoV‐2 infection and how bats are molecularly adapted to suppress these inflammasome responses. We also report an analysis of functionally important residues of inflammasome components that provide new clues of bat strategies to suppress inflammasome signaling and innate immune responses. As spillover of bat viruses may cause the emergence of new human disease outbreaks, the inflammasome regulation in bats and humans likely provides specific strategies to combat the pathogenic CoV infections.

Pathogenic coronaviruses (CoVs) have caused human respiratory infections and severe disease outbreaks in the past two decades. Recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans shows high transmissibility causing a wide range of clinical outcomes, named coronavirus disease-2019 (COVID-19), which emerged into an ongoing pandemic. Innate immune sensing of SARS-CoV-2 infection is critical for mounting antiviral and inflammatory responses to restrict the viral spread and initiate lung tissue repair processes. However, excessive cytokine and chemokine levels and dysregulated inflammatory immune cell function in the lungs are associated with respiratory failure and severe COVID-19. Thus, there is a tremendous need for understanding SARS-CoV-2-host interactions determining the aberrant inflammatory responses and loss of respiratory function. In this article, we discuss host innate immune responses determining dysregulated inflammation and immunopathology during SARS-CoV-2 infection. We also provide the perspective for the inflammatory cell death contribution for this immunopathology. Virus-induced acute host responses are complex, and elucidating this complex mechanism facilitates safe therapeutic interventions to alleviate inflammation-mediated immunopathology during pathogenic virus infections.