Breaking Bad: Inflammasome Activation by Respiratory Viruses

SIMPLE SUMMARY: Inflammasomes are multiprotein complexes that sense endogenous damage stimuli and diverse microbial pathogens, including viruses. A growing body of evidence shows that inflammasome activation by respiratory viruses, such as influenza virus and coronaviruses, is a double-edged sword. While inflammasomes are important for viral clearance and tissue injury recovery, an uncontrolled inflammasome activation leads to hyperinflammation and severe disease. This review summarizes the up-to-date knowledge on how respiratory viruses activate inflammasomes and how it influences disease pathogenesis. ABSTRACT: The nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family is a group of intracellular sensors activated in response to harmful stimuli, such as invading pathogens. Some NLR family members form large multiprotein complexes known as inflammasomes, acting as a platform for activating the caspase-1-induced canonical inflammatory pathway. The canonical inflammasome pathway triggers the secretion of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 by the rapid rupture of the plasma cell membrane, subsequently causing an inflammatory cell death program known as pyroptosis, thereby halting viral replication and removing infected cells. Recent studies have highlighted the importance of inflammasome activation in the response against respiratory viral infections, such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While inflammasome activity can contribute to the resolution of respiratory virus infections, dysregulated inflammasome activity can also exacerbate immunopathology, leading to tissue damage and hyperinflammation. In this review, we summarize how different respiratory viruses trigger inflammasome pathways and what harmful effects the inflammasome exerts along with its antiviral immune response during viral infection in the lungs. By understanding the crosstalk between invading pathogens and inflammasome regulation, new therapeutic strategies can be exploited to improve the outcomes of respiratory viral infections.