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Inflammasomes and Pyroptosis As Therapeutic Targets for COVID-19 Jeremy K

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Inflammasomes and Pyroptosis As Therapeutic Targets for COVID-19 Jeremy K Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19 Jeremy K. Y. Yap, Miyu Moriyama and Akiko Iwasaki This information is current as J Immunol published online 3 June 2020 of October 2, 2021. http://www.jimmunol.org/content/early/2020/06/02/jimmun ol.2000513 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists http://www.jimmunol.org/ • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: by guest on October 2, 2021 http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 3, 2020, doi:10.4049/jimmunol.2000513 Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19 x Jeremy K. Y. Yap,* Miyu Moriyama,† and Akiko Iwasaki†,‡, The inflammatory response to severe acute respiratory TLR7, and TLR8 in the endosome as well as retinoic acid– syndrome–related coronavirus 2 infection has a direct inducible gene I (RIG-I)–like receptors in the cytosol (2). impact on the clinical outcomes of coronavirus disease Suggestion of SARS-CoV-2 activating the inflammasomes 2019 patients. Of the many innate immune pathways and pyroptosis being at the core of pathogenesis comes from that are engaged by severe acute respiratory syndrome– the fact that lactate dehydrogenase (LDH) levels are highly related coronavirus 2, we highlight the importance of elevated in patients that go on to develop severe disease the inflammasome pathway. We discuss available phar- (Y. Han, H. Zhang, S. Mu, W. Wei, C. Jin, Y. Xue, C. Tong, Y. Zha, Z. Song, and G. Gu, manuscript posted on medRxiv). maceutical agents that target a critical component of Downloaded from inflammasome activation, signaling leading to cellular LDH is a cytosolic enzyme that is released to the extracellular pyroptosis, and the downstream cytokines as a prom- environment upon membrane rupture. In fact, LDH release is ising target for the treatment of severe coronavirus used to monitor pyroptosis (3). Additionally, cytokine re- leased as a result of inflammasome activation, IL-1b, as well as disease 2019–associated diseases. The Journal of Im- its response gene product, IL-1RA, are found to be elevated in munology, 2020, 205: 000–000. the sera of COVID-19 patients (4). The key to overcoming excessive inflammatory activity is to http://www.jimmunol.org/ hile the race for a vaccine against the severe target a crucial regulator of cellular inflammation while leaving acute respiratory syndrome–related coronavirus 2 the antiviral pathways intact. Pathogen- or alarmin-induced W (SARS-CoV-2) is in full swing, current treatments activation of nucleotide-binding oligomerization domain available for coronavirus disease 2019 (COVID-19) are limited (NOD)–like receptors leads to inflammasome assembly into a to supportive care. One of the greatest enigmas surrounding colossal molecular scaffold that generates a platform for the COVID-19 is the diverse disease trajectories of COVID-19 mass recruitment and activation of caspase-1 with the help patients. Some displayed little to no symptoms, whereas others of a “bridge” filament protein, the apoptosis-associated speck- develop severe fever and pneumonia, leading to acute respiratory like protein containing a caspase recruitment domain (ASC) by guest on October 2, 2021 distress syndrome and ultimately to death. It is becoming in- (Fig. 1). Proteolytic activation of caspase-1 subsequently catalyzes creasingly clear that the innate immune system is a major player the maturation and secretion of proinflammatory cytokines, in patients’ response to the virus infection. Serum levels of both specifically IL-1b and IL-18 (5). The most well-characterized pro- and anti-inflammatory cytokines are markedly higher in of the inflammasomes is the NOD-like receptor (NLR) family severe cases than in moderate cases of COVID-19, suggesting pyrin domain-containing 3 (NLRP3) inflammasome, which that a cytokine storm, also known as cytokine release syndrome, has been implicated in a plethora of diseases ranging from is associated with increasing disease severity (1). Additionally, autoinflammatory diseases to neurologic disorders. Impor- leukocytosis and lymphocytopenia are hallmark clinical features tantly, the NLRP3 inflammasome is also involved in antiviral of severe cases of COVID-19 (1). These observations allude to responses and virus-associated illnesses. an overdrive in inflammation as a mismanaged antiviral response It is presently unclear if SARS-CoV-2 activates the NLRP3 against SARS-CoV-2 that lead to poor clinical outcomes. inflammasome. However, taking lessons from its predecessor, SARS-CoV-2 is a positive-sense RNA virus. As such, its the severe acute respiratory syndrome–related coronavirus pathogen-associated molecular patterns will be recognized by (SARS-CoV), which caused the severe acute respiratory syn- RNA-sensing pattern recognition receptors, including TLR3, drome global epidemic between 2002 and 2003, was shown *School of Postgraduate Studies, International Medical University, 57000 Kuala Lumpur, Address correspondence and reprint requests to Prof. Akiko Iwasaki, Yale University Malaysia; †Department of Immunobiology, Yale University School of Medicine, New School of Medicine, 300 Cedar Street, TAC S655B, New Haven, CT 06519. E-mail Haven, CT 06520; ‡Department of Molecular, Cellular, and Developmental Biology, Yale address: [email protected] x University, New Haven, CT 06512; and Howard Hughes Medical Institute, Chevy Chase, Abbreviations used in this article: ASC, apoptosis-associated speck-like protein contain- MD 20815 ing a caspase recruitment domain; COVID-19, coronavirus disease 2019; E, envelope; ORCIDs: 0000-0002-5535-0732 (J.K.Y.Y.); 0000-0002-7824-9856 (A.I.). LDH, lactate dehydrogenase; NLR, NOD-like receptor; NLRP3, NOD-like receptor family pyrin domain-containing 3; NOD, nucleotide-binding oligomerization domain; Received for publication May 6, 2020. Accepted for publication May 15, 2020. NSAID, nonsteroidal anti-inflammatory drug; RIG-I, retinoic acid–inducible gene I; This work was supported by National Institutes of Health/National Institute of Allergy ROS, reactive oxygen species; SARS-CoV, severe acute respiratory syndrome–related and Infectious Diseases Grants R01AI127429, 75N93019C00051, 1R01NS111242, coronavirus; SARS-CoV-2, severe acute respiratory syndrome–related coronavirus 2; and U19AI089992 (to A.I.). Laboratory research regarding coronavirus disease 2019 TRAF3, TNFR-associated factor 3. was supported by the Women’s Health Research at Yale Pilot Project Program, a Fast Grant for COVID-19 from Emergent Ventures at the Mercatus Center (George Mason Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 University, Arlington, VA), the Mathers Foundation, and the Ludwig Family Founda- tion. A.I. is an investigator for the Howard Hughes Medical Institute. www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000513 2 BRIEF REVIEWS: INFLAMMASOMES AND PYROPTOSIS AS COVID-19 DRUG TARGETS Downloaded from http://www.jimmunol.org/ FIGURE 1. Activation of the NLRP3 inflammasome by SARS-CoV. SARS-CoV E protein induces Ca2+ leakage to the cytosol from Golgi storage, while ORF3a induces K+ efflux at the plasma membrane to the extracellular spaces. This imbalance in the ionic concentration within the cells, and the resultant ROS generated by damaged mitochondria, triggers NLRP3 inflammasome activation. In addition to inducing K+ efflux, ORF3a promotes inflammasome assembly through TRAF3-mediated ubiquitination of ASC. ORF8b interacts directly with leucine-rich repeat of NLRP3 to stimulate its activation independent of ion channel activity. Inflammasome activation induces the formation of gasdermin-D pores on the cell membrane, causing IL-1b and IL-18 secretion, and the influx of water by guest on October 2, 2021 molecules leading to cell swelling and subsequent rupture (pyroptosis). to express at least three proteins that activate the NLRP3 similarity with SARS-CoV and the amino acid sequences of inflammasome: envelope (E), ORF3a, and ORF8b. E protein SARS-CoV-2 and SARS-CoV E protein are 94.7% conserved, localizes at the membrane enfolding the Golgi complex and it is likely that SARS-CoV-2 could similarly activate the the endoplasmic reticulum–Golgi intermediate compartment NLRP3 inflammasome (14, 15). Interestingly, however, a and function as an ion channel (viroporin) that facilitates study on SARS-CoV-2 consensus sequence HKU-SZ-005b Ca2+ leakage to the cytosol (6). In contrast, ORF3a localizes showed a remarkable distinction in ORF8 from that of at the Golgi complex and plasma membrane, acting as a K+ SARS-CoV and a lack of the aggregation motif found in channel (7). As NLRP3 is sensitive to high cytosolic Ca2+ but SARS-CoV ORF8b that triggers NLRP3 activation (14). is instead inhibited by high K+ concentration, the viroporin ORF3a share 72% amino acid sequence identity between the activity of SARS-CoV presumably
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