The multifaceted roles of NLRP3-modulating proteins in virus infection

Abstract

The innate immune response to viruses is critical for the correct establishment of protective adaptive immunity. Amongst the many pathways involved, the NLRP3 [nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3)] inflammasome has received considerable attention, particularly in the context of immunity and pathogenesis during infection with influenza A (IAV) and SARS-CoV-2, the causative agent of COVID-19. Activation of the NLRP3 inflammasome results in the secretion of the proinflammatory cytokines IL-1β and IL-18, commonly coupled with pyroptotic cell death. While this mechanism is protective and key to host defense, aberrant NLRP3 inflammasome activation causes a hyperinflammatory response and excessive release of cytokines, both locally and systemically. Here, we discuss key molecules in the NLRP3 pathway that have also been shown to have significant roles in innate and adaptive immunity to viruses, including DEAD box helicase X-linked (DDX3X), vimentin and macrophage migration inhibitory factor (MIF). We also discuss the clinical opportunities to suppress NLRP3-mediated inflammation and reduce disease severity.

Intestinal microbiota analysis and network pharmacology reveal the mechanism by which Lianhua Qingwen capsule improves the immune function of mice infected with influenza A virus

“…Animal experiments have also confirmed that LHQW can reduce the viral load in the lungs of mice with viral pneumonia, reduce the expression of inflammatory factors in the lungs, and improve lung injury (Xia et al, 2020;Su et al, 2022). It is well known that viral clearance in the lung depends mainly on lymphocytes and macrophages (Bedi et al, 2022;Cammann et al, 2022;Harris and Borg, 2022;McGee et al, 2022;Verma et al, 2022;Wei et al, 2022;Zhang H. et al, 2022;Zhang M. et al, 2022); however, the present findings do not clarify how LHQW reduces the viral load in the lung and improves lung injury with viral pneumonia.…”

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

“…1 ) [ 44 – 47 , 52 , 53 , 75 ]. We posit that, in children, this age-dependent EPO elevation within the EPO evolutionary landscape, can effectively contain an acute SARS-CoV-2 infection and appropriately regulate the initial SARS-CoV-2-PAMP-induced NLRP3 inflammasome activation, while the ensuing SARS-CoV-2-induced RAAS hyperactivity with Ang II and aldosterone elevations could be leveraged to further enhance EPO secretion [ 35 – 37 ], rather than aggravating an ongoing NLRP3 inflammasome activation through pathways 2–5 [ 12 – 16 , 34 , 44 , 63 ]. Under the protection of this evolutionary landscape, consequent inflammatory and ischemic sequalae in the lung, heart, kidney, and central nervous system, can be prevented by EPO-mediated abrogation of further NLRP3 inflammasome activation involving pathways 2–5 [ 48 – 50 , 69 , 70 ].…”

Innate and adaptive immunity to SARS-CoV-2 and predisposing factors

“…The subsequent signals are derived from various inducers, among which potassium (K+) efflux is the necessary trigger for NLRP3 inflammasome assembly ( 43 ). Once activated by these signals, NLRP3 is oligomerized and assembled with apoptosis-associated speck-like protein containing a CARD (PYCARD, also known as ASC) and pro-caspase-1 ( 44 ).…”