key: cord-0991694-883h8xbd
authors: Nagaraja, Sahana; Jain, Disha; Kesavardhana, Sannula
title: Inflammasome regulation in driving COVID‐19 severity in humans and immune tolerance in bats
date: 2021-05-31
journal: J Leukoc Biol
DOI: 10.1002/jlb.4covhr0221-093rr
sha: 09958ac508e1992f3f490d32db795b39350bd023
doc_id: 991694
cord_uid: 883h8xbd

Coronaviruses (CoVs) are RNA viruses that cause human respiratory infections. Zoonotic transmission of the SARS‐CoV‐2 virus caused the recent COVID‐19 pandemic, which led to over 2 million deaths worldwide. Elevated inflammatory responses and cytotoxicity in the lungs are associated with COVID‐19 severity in SARS‐CoV‐2‐infected individuals. Bats, which host pathogenic CoVs, operate dampened inflammatory responses and show tolerance to these viruses with mild clinical symptoms. Delineating the mechanisms governing these host‐specific inflammatory responses is essential to understand host–virus interactions determining the outcome of pathogenic CoV infections. Here, we describe the essential role of inflammasome activation in determining COVID‐19 severity in humans and innate immune tolerance in bats that host several pathogenic CoVs. We further discuss mechanisms leading to inflammasome activation in human SARS‐CoV‐2 infection and how bats are molecularly adapted to suppress these inflammasome responses. We also report an analysis of functionally important residues of inflammasome components that provide new clues of bat strategies to suppress inflammasome signaling and innate immune responses. As spillover of bat viruses may cause the emergence of new human disease outbreaks, the inflammasome regulation in bats and humans likely provides specific strategies to combat the pathogenic CoV infections.

Spike (S) protein of the SARS-CoV-2 binds to the ACE2 receptor on the host cell membrane for its entry into the cell. The cell surface protease TMPRSS2 cleaves S protein to enable membrane fusion and entry of the virus. The replication of the viral RNA genome generates new SARS-CoV-2 virions. SARS-CoV-2 replication triggers the activation and assembly of the inflammasome and release of IL-1α, IL-1β, and IL-18 cytokines that are implicated in COVID-19 severity. Upon inflammasome activation, ASC oligomerizes into large filamentous structures/speck-like structures that recruit and activate CASP1 via CARD-mediated homotypic interactions. Active CASP1 cleaves pro-IL-1β and pro-IL-18 into mature forms. The CASP1 also cleaves GSDMD to liberate its N-terminal domain that oligomerizes into a pore-structure on the plasma membrane. GSDMD pores facilitate the passage of ions, water, and small molecules like IL-1β and IL-18. GSDMD pore formation licenses plasma membrane rupture through NINJ1 and triggers lytic cell death. Plasma membrane rupture is crucial for releasing large molecular weight DAMPs like IL-1α, LDH, and HMGB1. Inflammasome-independent cytokines, IL-6, IL-8, and TNF, secreted in response to SARS-CoV-2 infection, are associated with CoVID-19 severity led to severe disease outbreaks. 1-3 SARS-CoV-2 infection caused the ongoing pandemic and led to more than 2 million deaths worldwide.

SARS-CoV-2 infects the upper respiratory tract and binds to host receptor protein, angiotensin-converting enzyme 2 (ACE2), through its spike protein (S protein). [4] [5] [6] The membrane-bound host serine protease, transmembrane protease serine 2 (TMPRSS2), activates S protein to facilitate the entry of SARS-CoV-2 into the host cells (Fig. 1) . 4 The RNA genome of the SARS-CoV-2 will be released into the cytoplasm, where it replicates to generate new progeny of virions. 1,2 New virion particles transport through the secretion pathway to be released into extracellular space. In most cases, the SARS-CoV-2 infection is asymptomatic and, in some cases, it spreads to the lower respiratory tract causing pneumonia. 2,6 SARS-CoV-2 infection in some patients becomes severe and develops into acute respiratory distress syndrome leading to severe respiratory abnormalities and mortality. 2, 6 The SARS-CoV-2-induced moderate and severe disease in humans is collectively named coronavirus disease 2019 . 2, 6 The SARS-CoV-2-driven pathogenesis in human patients is a complex process. It is increasingly evident that excessive cytokine responses and infiltration of inflammatory cells, particularly inflammatory monocytes and neutrophils, are associated with COVID-19 severity. [7] [8] [9] Virus-induced cytopathic effects of lung epithelial cells in association with excessive inflammatory cytokines trigger acute lung injury and loss of respiratory function during COVID-19. [6] [7] [8] [9] [10] Endothelial barrier damage further leads to viral dissemination and spread to other organs. Dysregulated immune responses and increased inflammatory cytokine signatures also occur in other pathogenic RNA virus infections. 8, 11 Inflammation-driven excessive cytokine response in response to SARS-CoV-2 infection is highly associated with severe COVID-19 and a great effort has been put to understand and target these responses for alleviating COVID-19 severity.

Several studies report the association of excessive levels of proinflammatory cytokines, IL-1α, IL-1β, IL-6, IL-8, and TNF with COVID-19 severity. 10, [12] [13] [14] [15] [16] The mechanisms triggering these specific cytokine responses during SARS-CoV-2 remain elusive.

Inflammasomes are heteromeric multiprotein complexes that promote the activation of caspase-1 (CASP1) protease. 17, 18 The CASP1 activation in turn triggers the release of proinflammatory IL cytokines, IL-1β and IL-18, and damage-associated molecular patterns (DAMPs) like IL-1α, high mobility group box protein 1 (HMGB1), and lactate dehydrogenase (LDH) 19, 20 (Fig. 1 ). Activation of innate immune receptors, such as Nod-like receptors (NLRs) and AIM2-like receptors (ALRs), recruits an adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), to assemble the inflammasome complex and trigger proximity-induced CASP1 activation 18, 21 (Fig. 1) . The widely studied NOD-like receptor family pyrin domain (PYD) containing 3 (NLRP3) inflammasome requires 2 signals for its activation. The first signal provides priming of the NLRP3 inflammasome through inflammatory stimuli (like TLR or TNF receptor (TNFR)) engagement that promote NF-kB dependent expression of the NLRP3 and IL-1β. 22, 23 The priming signal also facilitates NLRP3 post-translational modifications favoring inflammasome assembly. [24] [25] [26] The second signal, known as the activation signal, is provided by pathogen-associated molecular patterns or cellular damage signals. 17, 27, 28 The second signal triggers NLRP3 inflammasome assembly, ASC recruitment, and activation of the CASP1. The ASC recruitment to NLRs or ALRs is mediated by PYD-mediated homotypic interactions. ASC polymerizes into large filamentous/speck-like structures, which further recruit CASP1 through caspase activation and recruitment domain (CARD)-mediated homotypic interactions between them 18,29 (Fig. 1 ). CASP1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18 forms. CASP1 also cleaves a pore-forming protein Gasdermin D (GSDMD) at the linker region of its N-and C-terminal domains to liberate it from its autoinhibitory conformation [30] [31] [32] (Fig. 1) . The N-terminal domain of the GSDMD is transported to the plasma membrane and oligomerize into a pore structure whose pore size is sufficient to enable the passage of small molecules and mature IL-1β and IL-18. 18, 19 The formation of GSDMD pores in turn promotes osmotic lysis and a lytic form of cell death called pyroptosis [30] [31] [32] (Fig. 1) . Earlier it was considered that the plasma membrane rupture and osmotic lysis that occur after GSDMD pore formation is a passive event. A recent study challenged this assumption and demonstrates that the plasma membrane rupture during pyroptosis is a programmed phenomenon regulated by nerve injury protein 1 (NINJ1) 33 (Fig. 1) . Thus, inflammasome activation triggers GSDMD pore formation and plasma membrane rupture for releasing large molecular weight DAMPs like HMGB1 and LDH.

A recent study demonstrates that a lectin protein, Galectin-1, is also a bona fide DAMP released in inflammatory cell death and promotes inflammation. 34 

The NLRP3 inflammasome is a widely studied complex and is known to be activated by RNA viruses. 17, 18, 23, 36 Inflammasome responses play an essential role in clearing viruses and virus-infected cells and promote tissue repair responses. 27, [36] [37] [38] [39] [40] In many RNA virus infection cases, viral RNAs generated during the replication process are sufficient to activate the NLRP3 inflammasome. 27, 36 In some cases, viral proteins also regulate the activation of the NLRP3 inflammasome. The inflammasome-induced cell death and the release of proinflammatory IL-1α, IL-1β, and IL-18 cytokines drive the recruitment of inflammatory immune cells to the infection site and promote viral clearance and tissue repair processes. 11, 27, [36] [37] [38] [39] [40] The increased levels of specific cytokines during severe COVID-19 suggest dysregulated inflammatory responses in pathogenesis progression. 7,10 Immune response profiling of moderate and severe COVID-19 patients indicates a correlation of inflammasomeassociated proinflammatory cytokines IL-1α and IL-1β with the severity of the disease. 8, 10, 12, 13, 41 Although several studies indicate the inflammasome role in severe COVID-19 disease progression, the activation of inflammasome in response to SARS-CoV-2 infection was obscure. A recent study demonstrated that the SARS-CoV-2 infection in primary human monocytes triggers CASP1 activation and IL-1β pro-duction, providing direct evidence for the activation of the inflammasome and proinflammatory cytokine release. 41 Similar to other RNA virus infections, replication of the SARS-CoV-2 is critical for the activation of the inflammasome. [39] [40] [41] [42] Experiments with MCC950, an inhibitor specific to NLRP3, suggest the specific role of NLRP3 inflammasome in SARS-CoV-2 induced CASP1 activation and IL-1β release. 41 Importantly, increased levels of LDH were seen in severe COVID-19 disease individuals indicating the lytic cell death programs (such as necroptosis and pyroptosis) after SARS-CoV-2 infection. 41 Older males with comorbidities show severe COVID-19 pathology after SARS-CoV-2 infection. 47 The comorbidities, like diabetes, obesity, cardiovascular diseases, cancers, digestive and respiratory system disease, and neurologic disorders, make older males more susceptible to COVID-19. [47] [48] [49] Physiologic aging is associated with chronic low-grade inflammation, which increases the risk of age-related diseases. 49, 50 The ligands that appear in aging promote increased NLRP3 inflammasome activation and chronic low-grade inflammation in older individuals. 50 Thus, NLRP3 inflammasome and chronic low-grade inflammation in older individuals predispose them to COVID-19 severity. 51 The higher risk of males compared with females indicates the role of

Pathogenic CoVs (SARS-CoV and SARS-CoV-2) trigger activation of the NLRP3 inflammasome in host cells. SARS-CoV-2 viroporins, ORF3a and E protein promote potassium (K + ) efflux or calcium (Ca 2+ ) release into the cytosol, which activates the NLRP3 inflammasome. These viroporins also stimulate NF-kB activation and transcriptional priming of NLRP3, IL-1b and IL-18. ORF7a and S proteins also promote priming and NF-kB activation. ORF8b of the SARS-CoV interacts with the LRR domain of the NLRP3 to promote its activation. The ORF3a and S protein of SARS-CoV-2 also engage NLRP3 inflammasome activation. NSP1 and NSP13 proteins of the SARS-CoV-2 abolish NLRP3 inflammasome activation and CASP1 mediated IL-1β release. The inflammasome activation and release of IL-1β and IL-18 correlate with COVID-19 severity in SARS-CoV-2 infected patients. Other inflammasomes or lytic cell death routes (ORF3a induced necrotic cell death) may also promote the release of DAMPs and excessive inflammatory responses. Bats have adapted to suppress NLRP3 inflammasome activation through regulating transcriptional priming and assembly of the inflammasome complex. This inflammasome suppression in bats dampens inflammation and confer immune tolerance to pathogenic CoVs steroid hormones in determining COVID-19 severity. 52 protein (ORF3a) is also a viroporin that promotes K+ efflux. 56 This further promotes mitochondrial reactive oxygen species and activation of the NLRP3 inflammasome and release of IL-1β. 56 Both E protein and ORF3a of SARS-CoV provide a priming signal to activate NF-kB signaling, which up-regulates the transcription of NLRP3, IL-1b, and other proinflammatory cytokines 57, 58 (Fig. 2) . In addition to K+ efflux and NF-kB activation, ORF3a also facilitates the TNFR-associated factor 3 (TRAF3)-mediated ubiquitination of the ASC to engage the NLRP3 inflammasome. 59, 60 The amino acid residues of E protein and ORF3a, critical for ion channel activity, NF-kB activation, and NLRP3 inflammasome assembly, are conserved in SARS-CoV and SARS-CoV-2 (Supplemental Fig. S1 ). E protein and ORF3a may likely trigger NLRP3 inflammasome activation in response to SARS-CoV-2 infection and promote COVID-19 severity. A new study demonstrates that the ORF3a of SARS-CoV-2 activates the NLRP3 inflammasome by regulating its expression and ASC-mediated inflammasome assembly. 61 The role of SARS-CoV-2 ORF3a in inflammasome-induced pathogenicity remains to be studied. Nevertheless, viroporins of pathogenic CoVs, which form ion channels, retain the ability to activate the NLRP3 inflammasome like other RNA viruses (Fig. 2) . In addition to promoting the NLRP3 inflammasome, the SARS-CoV ORF-3a can also trigger necrotic cell death. 62 The dual function of ORF-3a in promoting inflammatory cell death pathways (pyroptosis and necroptosis) may explain the inflammasome-independent release of LDH during SARS-CoV-2 infection. 41, 62 In addition to E protein and ORF3a, the spike protein (S protein) and ORF7a of the SARS-CoV promote NF-kB activation and inflammasome priming (Fig. 2) . 57, 63 The SARS-CoV-2 S protein also triggers inflammasome priming in COVID-19 patient-derived macrophages. 64 It appears that SARS-CoV-2-induced inflammasome activation is a complex process that involves multiple viral components. A recent study demonstrates that nonstructural protein (NSP) 1 and NSP13 of SARS-CoV-2 abolish NLRP3 inflammasome-mediated CASP1 activation and IL-1β release (Fig. 2) . 65 Thus, the SARS-CoV-2 also operates viral mechanisms counteracting inflammasome activation.

ORF8b protein of SARS-CoV acts like a virulence factor and is reported to interfere with IFN responses. 66 108 (Fig. 2) . Also, altered LRR domain function in bats contributes to the dampened NLRP3 inflammasome function in bats. 108 However, expression of ASC, CASP1, and IL-1β appeared to be not affected in bat immune cells like human cells. 108, 109 Because of NLRP3 priming and altered LRR domain defects, bat immune cells show lesser formation ASC speck assemblies and reduced release of IL-1β cytokine. 108 Besides, bat cells show impaired pyroptosis and LDH release compared with human cells. 108 Infection of bat immune cells with MERS-CoV fails to induce NLRP3 inflammasome activation and IL-1β release with unaltered viral loads. 108, 110 Thus, the bat's immune sys-tem is adapted to repress NLRP3 inflammasome activation and proinflammatory responses (Fig. 2) .

Flight in bats show high metabolic demand and mitochondrial oxidative phosphorylation activity. This results in DNA damage and the release of mitochondrial or nuclear self-DNA into the cytoplasm. Absent in melanoma 2 (AIM2) is a cytosolic DNA sensor that assembles inflammasome and triggers pyroptosis. Bats show complete loss of AIM2 and related Pyrin and HIN domain (PYHIN) gene family that play critical roles in nucleic acid sensing at multiple intracellular compartments. 104, 109, 111 Cyclic GMP-AMP synthase (cGAS) is also a cytosolic DNA sensor that produces cyclic GMP-AMP (cGAMP) upon DNA sensing. cGAS binds to stimulator of IFN genes (STING) protein that activates type I IFN responses. 112 Bats show dampened STING mediated IFN activation due to a mutation at the S358 phosphorylation site of the STING, which is essential for type I IFN response. 113 Thus, bat DNA sensing system is attenuated at multiple signaling pathways to curtail inflammasome activation and type I IFN responses. In addition, a recent study unravels variation in amino acid residues of bat CASP1 (D365N and R371Q) that reduces its enzymatic activity essential for IL-1β processing and pyroptosis. 109 A recent study by Goh et al. 109 identifies that some of the bat species, which show intact CASP1 func- 

Though the bats show reduced NLRP3 expression, they appear to show expression of the ASC, CASP1, and GSDMD proteins critical for the inflammasome activation by various innate immune receptors. 104, 108, 109 To fully delineate the bat adaptations in the inflammasome pathway, we mapped functionally critical residues of ASC, CASP1, and GSDMD in bats to comprehensively examine variations (Fig. 3) . The ASC consists of PYD and CARD domains that facilitate homotypic interactions and filamentous/speck-like structures. [115] [116] [117] [118] [119] The assembly of ASC and its polymerization is essential to recruit and activate the CASP1. 18, 117, 119 Our functional residue mapping analysis shows that the key residues essential for ASC oligomerization (PYD) and CASP1 recruitment (CARD) 117 appeared to be conserved with a notable exception at F59 and E130 residues (Fig. 3) . Bats that belong to Yangochiroptera suborder (M.

natalensis, M.davidii, and E. fuscus) show variation at one of the critical CARD (E130N) and PYD (F59S) residues required for ASC filament formation and CASP1 interaction (Fig. 3C) . We also observed a critical variation at one of the CARD residues (Y82H) of the CASP1 of multiple bat species (Fig. 3D) . INCA (inhibitory CARD) is a natural human CARD only protein that shares high similarity with the CARD domain of the CASP1 and interferes with its function. Interestingly, the INCA protein shows Y82H mutation (like bat CASP1), making it unsuitable for CARDmediated polymerization, but interfering with the CASP1 function. 118 These variations in ASC and CASP1 may interfere in their interaction and assembly of inflammasome complexes.

CASP1 contains a CARD domain, a large (p20) and small (p10) subunits. Interdomain linker regions separate these domains. 120-123 Once activated, CASP1 is self-cleaved at aspartic acid residues of the linker regions to generate enzymatically active p20 and p10 subunits. [120] [121] [122] [123] Mouse CASP1 shows variation at D119; however, D122 of the mouse CASP1, which is in close vicinity, compensates this variation and retains self-cleavage in linker regions 123 (Fig. 3D) . Our analysis indicates a notable variation at several cleavage site residues located in linker regions of bat CASP1 of both Yangochiroptera and Yinpterochiroptera suborders compared with human CASP1 (Fig. 3D) . We also did not observe any compensatory aspartic acid residues in adjacent amino acid sequences suggesting a possible exclusion of self-cleavage at these CASP1 regions. However, the residue crucial for CASP1 catalytic activity (C285) is highly conserved in bats and humans. We observed D365N and R371Q mutations in P. vampyrus and P. alecto, which were recently reported by Goh et al., 109 to affect the catalytic activity of the bat CASP1 (Fig. 3D) . Thus, it appears that a wide range of mutations may interfere with the bat CASP1 function following inflammasome activation.

GSDMD is a pore-forming protein that consists of a CASP1 cleavage site (D275) at the linker region of its N and C-terminal domains 31, 32 (Figs. 4A and 4B). CASP1-mediated cleavage of the GSDMD liberates the N-terminal domain that assembles into a pore structure on the cell membrane and triggers pyroptosis. 19, [30] [31] [32] Caspase-3 (CASP3) also cleaves the GSDMD N-terminal domain at D87, which abolishes poreforming activity 30, 124 (Figs. 4A and 4B) . The positively charged residues in α1-helix of the GSDMD N-terminal domain (residues R7, R10, and R11) are critical for its interaction with the cell membrane and subsequent oligomerization into a pore structure [125] [126] [127] (Figs. 4A and 4B) .

A recent study by Goh et al. 109 demonstrated the cleavage of bat GSDMD into N-and C-termini and pro-IL-1β into a mature form of IL-1β by caspases. Consistent with this study, we observed the cleavage sites of CASP1 and CASP3 in GSDMD are highly conserved in bats and humans (Fig. 4B) . However, R7 and R11 residues in α1-helix of the bat GSDMD are mutated to uncharged residues suggesting a potential restriction of pore formation and pyroptosis (Fig. 4B) . The caspase cleavage sites of IL-1β are conserved in bats and humans (Figs. 4A and 4C). Goh et al. 109 identified that the amino acid residues (residue positions 110, 111, and 118) surrounding the cleavage site D116 determine the IL-1β cleavage ability in M. davidii and P.alecto by CASP1. The cleavage ability of the IL-1β in these bat species shows an inverse complementary relationship with their CASP1 activity. 109 Previous studies indicate critical residues of IL-1β, which are necessary for binding to IL-1 receptor. [128] [129] [130] The IL-1 receptor binding residues of bat IL-1β are largely conserved; however, few variations were noted at I172, K209, and E221 residues in some of the bat species (Fig. 4C) . Overall, the analysis of functionally essential residues in ASC, CASP1, GSDMD, and IL-1β of bats reveals molecular adaptation of bats to restrict inflammasome mediated proinflammatory responses. Unlike the NLRP3, the expression of ASC, CASP1, and GSDMD is seen in bats, which might have forced them to acquire mutations at crucial residues to restrict inflammasome functions. What evolutionary pressures drive bat variations that dampen inflammasome activation? The causative triggers for the evolution of bat variations remain to be studied to suppress innate immune responses like inflammasome and STING activation.

The dampened inflammasome in bat immune tolerance and inflammasome activation in driving COVID-19 severity suggests inflammasome as a target for alleviating disease severity in humans. Also, monitoring circulating inflammasome cytokines in humans may assist in identifying individuals who are likely predisposed for COVID-19 severity.

Human cells operate diverse innate immune receptors, ALRs and NLRs, to engage inflammasome assembly and pyroptosis. Thus, human res- 

The authors of this manuscript thank all the research groups who made substantial contributions to understanding inflammasome biology and its impact on human and bat inflammatory responses. S.K. laboratory is supported by funds from the Indian Institute of Science (IISc) and

Infosys Foundation, Bengaluru, India.

The authors declare no conflicts of interest.

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