Inflammasome regulation in driving COVID-19 severity in humans and immune tolerance in bats

Abstract

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.

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Significant increases in the CASP1 expression in patients with acute COVID-19 were reported in previous transcriptomic studies ( 236 , 237 ). Indeed, activation of CASP1 by activating inflammasomes in response to the SARS-CoV-2 infection activates IL1B and IL18 and contributes to hypercytokinemia in COVID-19 patients ( 238 – 240 ). Besides, activation of CASP1 promotes pyroptosis (a highly inflammatory and Caspase-1-dependent form of programmed cell death), which can lead to secretion of a wide range of inflammatory mediators ( 241 , 242 ).…”

Alcohol use disorder as a potential risk factor forCOVID‐19 severity: A narrative review

“…Interestingly, bats were shown to lack an NLRP3 response making them an ideal host reservoir for SARS viruses (Ahn et al, 2019). A large body of data now supports a critical role for NLRP3 inflammasome activation in SARS infection as well as COVID‐19 and the cytokine storm pathogenesis in both coronavirus diseases (Freeman & Swartz, 2020; Lee et al, 2020; Nagaraja et al, 2021; Yap et al, 2020; Zhao & Zhao, 2020). Circulating monocyte activation of NLRP3 has been proposed as a marker of COVID‐19 severity (Courjon et al, 2021).…”

SARS-CoV2 Infection and the Importance of Potassium Balance

“…Ion disturbance, mediated by virioporins, is central to the mechanism of action of a range of viruses from influenza, and rhinovirus to COVID-19 and HIV ( 8 ), and a number of RNA viruses modulate activity of the NLRP3 inflammasome in a potassium-dependent manner ( 65 , 66 ). In bats, dampening of the inflammasome and proinflammatory responses confers tolerance to a range of RNA viruses, suggesting that modulating the inflammasome may prove a useful therapeutic target for reducing disease severity in humans too ( 10 ).…”

“…It does so by triggering the cell-intrinsic Nod-like receptor family, pyrin domaincontaining 3 (NLRP3) inflammasome (7)(8)(9), which promotes cytokine release. Inflammasome responses play fundamental roles in clearing viruses and promoting tissue repair (10), however, hyperactivation of this immune response, gives rise to the devastating "cytokine storm" that is associated with severe infection, and a major cause of death (11).…”