SARS-CoV-1-mediated effects on programmed cell death

SARS-CoV-1-mediated effects on programmed cell death Programmed cell death (PCD) pathways, including pyroptosis, apoptosis, and necroptosis, are induced in infected host cells as an integral part of host defense to restrict microbial infections and regulate inflammatory responses (reviewed in Jorgensen I et al. 2017; Galluzzi L et al. 2018). Apoptosis is a noninflammatory form of cell death driven by the initiator caspase‑mediated cleavage of executioner caspase‑3 and ‑7. It facilitates degradation of the cellular contents but these are not released to the extracellular space. Necroptosis and pyroptosis are highly inflammatory forms of cell death that lead to cell lysis and release of pro‑inflammatory cytokines such as interleukin (IL)‑1β, tumour necrosis factor alpha (TNF‑α), IL6, IL18 and cellular contents, which can cause severe inflammation (reviewed in Jorgensen I et al. 2017; Galluzzi L et al. 2018; Pasparakis M & Vandenabeele P 2015). Gasdermins (GSDMs) exert pore‑forming activity in inflammasome‑dependent pyroptosis, while the mixed lineage kinase domain‑like (MLKL) protein functions as the executioner during necroptosis (Shi J et AL. 2015; Upton JW et al. 2017). Inflammation is a fundamental protective mechanism in elimination of microorganisms, and is normally tightly regulated by certain mediators, in particular IL10, to promote resolution of inflammation (reviewed in Sugimoto MA et al. 2016). Microbial pathogens are able to trigger and/or modulate host PCD and inflammatory response through multiple mechanisms.This Reactome module describes the roles of severe acute respiratory syndrome‑associated coronavirus type 1 (SARS‑CoV‑1) 3a, E, and 7a proteins in the induction of host cell death pathways. SARS‑CoV‑1 open reading frame‑3a (3a) binds host receptor interacting serine/threonine protein kinase 3 (RIPK3), facilitating RIPK3 oligomerization and the ion channel functionality of viral 3a, inducing inflammatory cell death and release of cellular contents (Yue Y et al. 2018). Enhanced production and release of proinflammatory cytokines leads to the cytokine storm that is considered to play a major role in SARS‑CoV type 1and 2 infections (reviewed in Channappanavar R & Perlman S 2017; Yang L et al. 2020). The module also describes induction of apoptosis by SARS‑CoV‑1 E and 7a proteins through their interaction with anti‑apoptotic BCL2L1 (Yang Y et al. 2005; Tan YX et al. 2007). Low levels of BCL2L1 may lead to enhanced function of pro‑apoptotic molecules, contributing to the depletion of T lymphocytes by apoptosis (Yang Y et al. 2005). This may lead to the lymphopenia observed in SARS patients, particularly in severe cases (Diao B et al. 2020; Chen Z & Wherry EJ 2020).