key: cord-333606-5z3kumu9 authors: Lee, SangJoon; Channappanavar, Rudragouda; Kanneganti, Thirumala-Devi title: Coronaviruses: Innate Immunity, Inflammasome Activation, Inflammatory Cell Death, and Cytokines date: 2020-10-15 journal: Trends Immunol DOI: 10.1016/j.it.2020.10.005 sha: doc_id: 333606 cord_uid: 5z3kumu9 The innate immune system acts as the first line of defense against pathogens, including coronaviruses. SARS-CoV and MERS-CoV are epidemic zoonotic coronaviruses that emerged at the beginning of the 21st century. The recently emerged virus SARS-CoV-2 is a novel strain of coronavirus that has caused the COVID-19 pandemic. Scientific advancements made by studying the SARS-CoV and MERS-CoV outbreaks have provided a foundation for understanding pathogenesis and innate immunity against SARS-CoV-2. In this review, we focus on our present understanding of innate immune responses, inflammasome activation, inflammatory cell death pathways, and cytokine secretion during SARS-CoV, MERS-CoV, and SARS-CoV-2 infection. We also discuss how the pathogenesis of these viruses influences these biological processes. CoV, as infection with this virus recapitulates several aspects of the severe human disease, including pulmonary pathology, morbidity, and mortality [19] . For infections with MERS-CoV and SARS-CoV-2, human DPP4 transgenic mice with a mouse-adapted strain of MERS-CoV and human ACE2 (hACE2) transgenic mice with SARS-CoV-2 have been used to replicate several features of severe human disease, including pulmonary pathology and mortality [20, 21] . Limitations with these systems have been noted. In human DPP4 transgenic mice, the lung disease that develops in response to the mouse-adapted strain of MERS-CoV infection may depend on species-specific mutations in the new host, which may not recapitulate all aspects of the human infection [20] . A potential disadvantage of studying SARS-CoV-2 in hACE2 transgenic mice is that the brain infection observed in mice that succumb to disease may not reflect the pathogenesis of SARS-CoV-2 in humans [21] . Additionally, hACE2 is expressed under the control of the HFH4/FOXJ1 promoter in these mice, which is largely specific to epithelial cells [21] . Consequently, hematopoietic cells from hACE2 transgenic mice cannot be infected with SARS-CoV-2 [21] . Despite these limitations, significant work has been done to molecularly characterize the innate immune pathways involved in detecting and controlling CoV infections. patients with severe or critical COVID-19 also found that reduced amounts of type I IFNs in the blood during SARS-CoV-2 infection were associated with increased viral load in the blood, and exacerbation of the inflammatory response [38] . Furthermore, data from whole genome sequencing of patients with life-in driving or contributing to infection outcomes, and certainly warrant further investigation. Innate immune cells play a major role in anti-viral immunity, inflammatory signaling, and cytokine production. Among the proinflammatory cytokines, IL-1 Pyroptosis is an inflammasome-mediated form of inflammatory cell death [3] . Inflammasome assembly leads to the activation of inflammatory caspases Table 2) . Table 2) , and additional work is needed to determine whether this is occurring. Pyroptosis and necroptosis are similar in that they are lytic forms of cell death driven by the GSDMD pore and MLKL channel, respectively, that release proinflammatory cytokines and other cellular factors to alert the surrounding cells of danger and to recruit innate and adaptive inflammatory cells [54, 55]. Apoptosis was originally thought to be a less inflammatory form of cell death that disassembled the cell via membrane blebbing to avoid directly releasing cellular contents [58]. However, more recent studies have suggested that it is not always immunologically silent, as there is crosstalk between apoptotic proteins and lytic cell death executioners [58] . Apoptosis is driven by initiator caspase-8, -9, and -10 cleavage of executioner caspase-3 and -7. The apoptotic caspase-3 has been reported to activate gasdermin E (GSDME) to induce a lytic form of cell death Table 2) . Overt activation of inflammatory cell death pathways may lead to critical tissue One of the goals of the innate immune response is to use PRRs to recognize pathogenshere, viral agentsand ultimately trigger an inflammatory response and programmed cell death to limit viral replication and promote clearance. In Another study also showed that bats have a mutation in an essential and highly inflammation [113] , suggesting that sex-based differences might affect inflammation and susceptibility to CoV infection. These results suggest that innate host protection may play an important role in directing CoV disease resistance. We have highlighted the sensing of different CoVs by the  Optimal NLRP3 inflammasome activation is beneficial for the host but aberrant activation may lead to detrimental CoV infection outcomes.  Specific CoV infections can activate inflammatory cell death (PANoptosis), thereby inducing cytokine release.  CoV disease tolerance occurs in age-, species-, and sex-dependent manners.  More studies are needed to define the innate immune response, specifically during SARS-CoV-2 infection, and to inform the development of candidate therapeutics. J o u r n a l P r e -p r o o f Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death Points of control in inflammation Bat origin of human coronaviruses Coronaviruses: an overview of their replication and pathogenesis A pneumonia outbreak associated with a new coronavirus of probable bat origin Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China The pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive epidemiological analysis of data from the Saudi Ministry of Health Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Effective treatment of severe COVID-19 patients with tocilizumab Compassionate Use of Remdesivir for Patients with Severe Covid-19 e393-e400 Heart Acute myocardial injury and chronic damage to the cardiovascular system [11, 135] Liver Steatosis and abnormal liver function with AST and ALT Intestine Gastrointestinal symptoms e.g. diarrhea and severe acute ulcerative colitis CoV viral proteins can function as cytosolic pathogen-associated molecular patterns (PAMPs) and stimulate inflammasome assembly, resulting in activation of caspase-1. Active caspase-1 then cleaves pro-IL-1pro-IL-18, and gasdermin D (GSDMD). The N-terminal fragment of GSDMD may then oligomerize within membranes to form membrane pores and execute pyroptosis SARS-CoV-2, and MHV infection initiate a signaling cascade mediated by caspase-8 activation. Caspase-8 activates caspase-3 to drive apoptosis HCoV-OC43 and MHV infection initiate necroptosis, a receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 complex-dependent form of inflammatory cell death that depends on activation of the protein mixed lineage kinase domain-like pseudokinase (MLKL) to form channels in the membrane We apologize to our colleagues in the field whose work could not be cited due to space limitations. We thank all the members of the Kanneganti laboratory for their comments and suggestions and Rebecca Tweedell, PhD, for scientific editing and writing support. Work from our laboratory is supported by the US National Institutes of Health (AI101935, AI124346, AR056296, and CA253095 to