Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

Another antiviral innate immune response that is activated during ion flux is the complex termed the "inflammasome." An inflammasome is a caspase-activating complex that upon induction results in caspase-1 activation and pro-inflammatory cytokines secretion [175] . There are several distinct inflammasomes that can be activated via different viral factors and pattern recognition receptors (PRR) [176] . One of the inflammasome complexes that can be activated via disturbances in intracellular ionic concentration in addition to the pathogen-associated molecular patterns (PAMPs) is the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome [177, 178] . Several respiratory viruses are known to activate NLRP3 inflammasome in the lung during infection by causing disturbances to the cellular potassium and calcium ion homeostasis via viroporins [179] . IAV is the most common activator of the NLRP3 inflammasome, in which it induces the maturation of caspase-1 via dsRNA [180] and subsequent secretion of pro-inflammatory cytokine, such as IL-1β [181, 182] . Activation of NLRP3 inflammasome requires two signals [183] . In addition to the dsRNA, M2 provides the second signal by altering the ionic concentration within the TGN via its proton channel activity [184] . The hRSV SH viroporin also induces NLRP3 inflammasome activation in a similar manner. Wild-type hRSV induces caspase-1 maturation and IL-1β secretion, which can be prevented using a SH-defective mutant or by treating the cells with ion channel inhibitors, emphasizing the importance of SH ion channel activity in inflammasome activation [185] . The Encephalomyocarditis virus (EMCV), a member of the Picornaviridae, encodes a viroporin, 2B, similar to the poliovirus 2B viroporin [186] . Expression of 2B alone is sufficient to induce the efflux of calcium from the ER into the cytoplasm, which is a prerequisite for the activation of inflammasome and subsequent IL-1β secretion. Treatment with the calcium ion chelator BAPTA-AM completely inhibited the release of IL-1β, suggesting that 2B is solely responsible for EMCV-induced inflammasome activation [187] .