Biology subjects

Brodsky, I. E.

Publications and source records attributed to Brodsky, I. E..

15 recordsLinked to original sources

bioRxiv2023

Sequentially activated death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling

The Yersinia virulence factor YopJ potently inhibits immune signaling in macrophages by blocking activation of the signaling kinases TAK1 and IKK. In response, macrophages trigger a backup pathway of host defense that mediates cell death via the apoptotic enzyme caspase-8 and pyroptotic enzyme caspase-1. While caspase-1 is normally activated within multiprotein inflammasome complexes that contain the adaptor ASC and NLRs, which act as sensors of pathogen virulence, caspase-1 activation following Yersinia blockade of TAK1/IKK surprisingly requires caspase-8 and is independent of all known inflammasome components. Here, we report that caspase-1 activation by caspase-8 requires both caspase-8 catalytic and auto-processing activity. Intriguingly, while caspase-8 serves as an essential initiator of caspase-1 activation, caspase-1 amplifies its own activation through a feed-forward loop involving auto-processing, caspase-1-dependent cleavage of the pore-forming protein GSDMD, and subsequent activation of the canonical NLRP3 inflammasome. Notably, while caspase-1 activation and cell death are independent of inflammasomes during Yersinia infection, IL-1{beta} release requires the canonical NLPR3 inflammasome. Critically, activation of caspase-8 and activation of the canonical inflammasome are kinetically and spatially separable events, as rapid capase-8 activation occurs within multiple foci throughout the cell, followed by delayed subsequent assembly of a single canonical inflammasome. Importantly, caspase-8 auto-processing normally serves to prevent RIPK3/MLKL-mediated necroptosis, and in caspase-8s absence, MLKL triggers NLPR3 inflammasome activation and IL-1{beta} release. Altogether, our findings reveal that functionally interconnected but temporally and spatially distinct death complexes differentially mediate pyroptosis and IL-1{beta} release to ensure robust host defense against pathogen blockade of TAK1 and IKK. One Sentence SummaryYersinia-induced cell death and IL-1{beta} release are driven by spatially and temporally distinct but functionally connected death complexes.

immunology↗

bioRxiv2023

Forward genetic screening in engineered colorectal cancer organoids identifies novel regulators of metastasis

Cancer is the second leading cause of death globally, due primarily to metastatic dissemination and colonization of distal sites. Recurrent genetic drivers of metastasis are elusive, suggesting that, unlike the stereotyped mutations promoting primary tumor development, drivers of metastasis may be variable. Here, we interrogate pathways governing metastasis through CRISPR/Cas9-based forward genetic screening in a genetically defined colorectal adenocarcinoma tumor organoid (tumoroid) model using ex vivo invasion screens and orthotopic, in vivo screens for gain of metastatic potential. We identify Ctnna1 and Bcl2l13 as bona fide metastasis suppressors. CTNNA1 loss promotes carcinoma cell invasion and migration through an atypical EMT-like mechanism, whereas BCL2L13 loss promotes cell survival after extracellular matrix detachment and non-cell-autonomous macrophage polarization. Ultimately, this study provides a proof-of-principle that high-content forward genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of colon cancer metastasis.

cancer biology↗

bioRxiv2023

Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages

Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.

microbiology↗

bioRxiv2023

Blockade of IKK signaling induces RIPK1-independent apoptosis in human cells

Regulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gramnegative bacterial pathogens in the Yersinia genus disrupt NF-{kappa}B signaling via translocated effectors injected by a type III secretion system (T3SS), thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection, Yersinia blockade of NF-{kappa}B signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival. Unexpectedly, we find that human macrophages undergo apoptosis independently of RIPK1 in response to Yersinia or chemical blockade of IKK/{beta}. Instead, IKK blockade led to decreased cFLIP expression, and overexpression of cFLIP contributed to protection from IKK blockade-induced apoptosis in human macrophages. Importantly, IKK blockade also induces RIPK1 kinase-independent apoptosis in human T cells and human pancreatic cells. Altogether, our data indicate that, in contrast to murine cells, blockade of IKK activity in human cells triggers a distinct apoptosis pathway that is independent of RIPK1. These findings have implications for the contribution of RIPK1 to cell death in humans and the efficacy of RIPK1 inhibition in human diseases.

immunology↗

bioRxiv2023

TLR priming licenses NAIP inflammasome activation by immunoevasive ligands

NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family, CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages, and not thought to be regulated by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR) stimulation upregulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. TLR-induced NLRC4 upregulation and NAIP detection of evasive ligands required p38 MAPK signaling. In contrast, TLR priming in human macrophages did not upregulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for NAIP/NLRC4 inflammasome activation and enables inflammasome responses against immunoevasive or suboptimal NAIP ligands. Significance StatementCytosolic receptors in the neuronal apoptosis inhibitor protein (NAIP) family detect bacterial flagellin and components of the type III secretion system (T3SS). NAIP binding to its cognate ligand engages the adaptor molecule NLRC4 to form NAIP/NLRC4 inflammasomes culminating in inflammatory cell death. However, some bacterial pathogens evade NAIP/NLRC4 inflammasome detection, thus bypassing a crucial barrier of the immune system. Here, we find that, in murine macrophages, TLR-dependent p38 MAPK signaling increases NLRC4 expression, thereby lowering the threshold for NAIP/NLRC4 inflammasome activation in response to immunoevasive NAIP ligands. Human macrophages were unable to undergo priming-induced upregulation of NLRC4 and could not detect immunoevasive NAIP ligands. These findings provide a new insight into species-specific regulation of the NAIP/NLRC4 inflammasome.

molecular biology↗

bioRxiv2023

A TNF-IL-1 circuit controls Yersinia within intestinal granulomas

SummaryMonocytes restrict Yersinia infection within intestinal granulomas. Here, we report that monocyte-intrinsic TNF signaling drives production of IL-1 that signals to non-hematopoietic cells to control intestinal Yersinia infection within granulomas. Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance of Yersinia within intestinal pyogranulomas, but how monocytes mediate Yersinia restriction is poorly understood. Here, we demonstrate that TNF signaling in monocytes is required for bacterial containment following enteric Yersinia infection. We further show that monocyte-intrinsic TNFR1 signaling drives production of monocyte-derived interleukin-1 (IL-1), which signals through IL-1 receptor on non-hematopoietic cells to enable pyogranuloma-mediated control of Yersinia infection. Altogether, our work reveals a monocyte-intrinsic TNF-IL-1 collaborative circuit as a crucial driver of intestinal granuloma function, and defines the cellular target of TNF signaling that restricts intestinal Yersinia infection.

immunology↗

bioRxiv2023

Yersinia Type III-Secreted Effectors Subvert Caspase-4-dependent Inflammasome Activation in Human Cells

Yersinia are gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to inject Yersinia outer proteins (Yops) into the host cytosol to subvert essential components of innate immune signaling. However, Yersinia virulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection. Yersinia activation and evasion of inflammasomes have been characterized in murine macrophages but remain poorly defined in human cells, particularly intestinal epithelial cells (IECs), a primary site of intestinal Yersinia infection. In contrast to murine macrophages, we find that in both human IECs and macrophages, Yersinia pseudotuberculosis T3SS effectors enable evasion of the caspase-4 inflammasome, which senses cytosolic lipopolysaccharide (LPS). The antiphagocytic YopE and YopH, as well as the translocation regulator YopK, were collectively responsible for evading inflammasome activation, in part by inhibiting Yersinia internalization mediated by YadA and {beta}1-integrin signaling. These data provide insight into the mechanisms of Yersinia-mediated inflammasome activation and evasion in human cells, and reveal species-specific differences underlying regulation of inflammasome responses to Yersinia. ImportanceYersinia are responsible for significant disease burdens in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics (Yersinia pestis plague). Together with rising antibiotic resistance rates, there is a critical need to better understand Yersinia pathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans. Here, we dissect human intestinal epithelial cell and macrophage inflammasome responses to Yersinia pseudotuberculosis. Our findings provide insight into species- and cell type-specific differences in inflammasome responses to Yersinia.

microbiology↗

bioRxiv2022

Noncanonical inflammasome assembly requires caspase-11 catalytic activity and intra-molecular autoprocessing

Inflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammsasomes. Inflammasomes are large oligomeric complexes that recruit caspases to undergo proximity-induced autoprocessing, leading to formation of the enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high molecular weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. However, the cellular correlates of Casp11 oligomerization and whether Casp11 forms an LPS-induced SMOC within cells remain unknown. Using fluorescently labeled Casp11, we found that LPS transfection of macrophages induced Casp11 speck formation, providing direct evidence that Casp11 forms LPS-induced specks in macrophages. Unexpectedly, we found that catalytic activity was required for Casp11 to form LPS-induced specks in macrophages. Importantly, both catalytic activity and autoprocessing were required for Casp11 speck formation in an ectopic expression system, and Casp11 processing via an exogenous protease was sufficient to induce Casp11 speck formation. These data reveal a previously-undescribed role for Casp11 catalytic activity and self-cleavage in non-canonical inflammasome assembly and indicate that Casp11 catalytic activity and autoprocessing occur upstream of, and mediate, Casp11 oligomerization. Our data provide new insight into the molecular requirements for assembly of Casp11 noncanonical inflammasome complexes.

immunology↗

bioRxiv2022

TNF licenses macrophages to undergo rapid caspase-1, -11, and -8-mediated cell death that restricts Legionella pneumophila infection

The inflammatory cytokine tumor necrosis factor (TNF) is associated with host defense against many intracellular pathogens, including Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires Disease and predominantly affects individuals with a suppressed immune system, such as those receiving therapeutic TNF blockade to treat autoinflammatory disorders. TNF induces pro-inflammatory gene expression, cellular proliferation, and survival signals in certain contexts, but can also trigger programmed cell death in others. It remains unclear, however, which of the many downstream activities of TNF contribute to control of intracellular bacterial pathogens like Legionella. In this study, we demonstrate that TNF signaling licenses macrophages to die rapidly in response to Legionella infection. We find that TNF-licensed cells undergo rapid gasdermin-dependent, pyroptotic death downstream of inflammasome activation. We also find that TNF signaling upregulates components of the inflammasome response, and that the caspase-11 mediated non-canonical inflammasome is the first inflammasome to be activated, with caspase-1 and caspase-8 mediating delayed pyroptotic death. We find that all three caspases are collectively required for optimal TNF-mediated restriction of bacterial replication in macrophages. Furthermore, caspase-8 is required for control of pulmonary Legionella infection. These findings reveal a TNF-dependent mechanism in macrophages for the activation of rapid cell death that is collectively mediated by caspases-1, -8, and -11 and subsequent restriction of Legionella infection.

microbiology↗

bioRxiv2022

Inflammatory monocytes promote pyogranuloma formation to counteract Yersinia blockade of host defense

Granulomas are organized immune cell aggregates that form in response to chronic infection or antigen persistence. Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signaling and phagocytosis, inducing formation of neutrophil-rich pyogranulomas within lymphoid tissues. Here, we uncover that Yp triggers pyogranuloma formation within the murine intestinal mucosa, a site not known to contain such structures. Mice lacking circulating monocytes fail to form defined pyogranulomas, have defects in neutrophil activation, and succumb to Yp infection. Yersinia lacking the virulence factors that block phagocytosis did not induce pyogranulomas, indicating that intestinal pyogranulomas form in response to Yp disruption of phagocytosis. Notably, mutation of a single anti-phagocytic virulence factor, YopH, restored pyogranuloma formation and control of Yp infection in monocyte-deficient mice, demonstrating that monocytes override YopH-dependent blockade of innate immune defense. This work reveals an unappreciated site of Yersinia intestinal invasion, and defines host and pathogen drivers of intestinal granuloma formation.

microbiology↗

bioRxiv2022

Arresting microbiome development limits immune system maturation and resistance to infection.

Disruptions to the intestinal microbiome during weaning lead to long-term negative effects on host immune function. However, the critical host-microbe interactions occurring during weaning required for healthy immune system development remain poorly understood. We find that restricting microbiome maturation during weaning leads to stunted immune system development and increased susceptibility to enteric infection. We developed a gnotobiotic mouse model of the early-life microbiome designated as Pediatric Community (PedsCom). This nine-member consortium of microbes derived from intestinal microbiomes of preweaning mice stably colonized germfree adult mice and was efficiently transmitted to offspring for multiple generations. Unexpectedly, the relative abundance of PedsCom microbes were largely unaffected by the transition from a milk-based to a fiber rich solid food diet. PedsCom mice developed less peripheral regulatory T cells and Immunoglobulin A, hallmarks of microbiota-driven immune system development. Consistent with defects in maturation, adult PedsCom mice retain high susceptibility to salmonella infection characteristic of young mice and humans. Altogether, our work illustrates how the post-weaning transition in intestinal microbiome composition contributes to normal immune maturation and protection from enteric infection. Accurate modelling of the pre-weaning microbiome provides a window into the microbial requirements of healthy immune development and suggests an opportunity to design microbial interventions at weaning to improve immune system development in human infants. One Sentence SummaryArresting microbiome development stunts immune ontogeny

immunology↗

bioRxiv2021

Position-specific secondary acylation determines detection of lipid A by murine TLR4 and caspase-11

Immune sensing of the Gram-negative bacterial membrane glycolipid lipopolysaccharide (LPS) is both a critical component of host defense against Gram-negative bacterial infection, and a contributor to hyper-inflammatory response, leading to sepsis and death. Innate immune activation by LPS is due to the lipid A moiety, an acylated di-glucosamine molecule that can activate inflammatory responses via the extracellular sensor TLR4/MD2 or the cytosolic sensor caspase-11 (Casp11). The number and length of acyl chains present on bacterial lipid A structures vary across bacterial species and strains, which affects the magnitude of TLR4 and Casp11 activation. TLR4 and Casp11 are thought to respond similarly to various lipid A structures, as tetra-acylated lipid A structures do not activate either sensor, whereas hexa-acylated structures activate both sensors. However, direct analysis of extracellular and cytosolic responses to the same sources and preparations of LPS/lipid A structures have been limited, and the precise features of lipid A that determine the differential activation of each receptor remain poorly defined. To address this question, we used rationally engineered lipid A isolated from a series of bacterial acyl-transferase mutants that produce novel, structurally defined molecules. Intriguingly, we find that the location of specific secondary acyl chains on lipid A resulted in differential recognition by TLR4- or Casp11, providing new insight into the structural features of lipid A required to activate either TLR4- or Casp11. Our findings indicate that TLR4 and Casp11 sense non-overlapping areas of lipid A chemical space, thereby constraining the ability of Gram-negative pathogens to evade innate immunity.

immunology↗

bioRxiv2021

Human TLR4 and noncanonical inflammasome differ in their ability to respond to distinct lipid A variants

Detection of Gram-negative bacterial lipid A by the extracellular sensor, MD-2/TLR4 or the intracellular inflammasome sensors, CASP4 and CASP5, induces robust inflammatory responses. The chemical structure of lipid A, specifically the phosphorylation and acylation state, varies across and within bacterial species, potentially allowing pathogens to evade or suppress host immunity. Currently, it is not clear how distinct alterations in the phosphorylation or acylation state of lipid A affect both human TLR4 and CASP4/5 activation. Using a panel of engineered lipooligosaccharides (LOS) derived from Yersinia pestis with defined lipid A structures that vary in their acylation or phosphorylation state, we identified that differences in phosphorylation state did not affect TLR4 or CASP4/5 activation. However, the acylation state differentially impacted TLR4 and CASP4/5 activation. Specifically, all of the examined tetra-, penta-, and hexa-acylated LOS variants activated CASP4/5-dependent responses, whereas TLR4 responded to penta- and hexa-acylated LOS but did not respond to tetra-acylated LOS or pentaacylated LOS lacking the secondary acyl chain at the 3 position. As expected, lipid A alone was sufficient for TLR4 activation; however, human macrophages required both lipid A and the core oligosaccharide to mount a robust CASP4/5 inflammasome response. Our findings show that human TLR4 and CASP4/5 detect both shared and non-overlapping LOS/lipid A structures, which enables the innate immune system to recognize a wider range of bacterial LOS/lipid A, thereby constraining the ability of pathogens to evade innate immune detection.

immunology↗

bioRxiv2021

Salmonella Typhimurium induces NAIP/NLRC4- and NLRP3/ASC-independent, caspase-1/4-dependent inflammasome activation in human intestinal epithelial cells

Salmonella enterica serovar Typhimurium is a gram-negative pathogen that causes diseases ranging from gastroenteritis to systemic infection and sepsis. Salmonella uses type III secretion systems (T3SSs) to inject effectors into host cells. While these effectors are necessary for bacterial invasion and intracellular survival, intracellular delivery of T3SS products also enables detection of Salmonella by cytosolic immune sensors. Upon detecting translocated Salmonella ligands, these sensors form multimeric complexes called inflammasomes, which activate caspases that lead to proinflammatory cytokine release and pyroptosis. In particular, the Salmonella T3SS needle, inner rod, and flagellin proteins activate the NAIP/NLRC4 inflammasome in murine intestinal epithelial cells (IECs), which leads to restriction of bacterial replication and extrusion of infected IECs into the intestinal lumen, thereby preventing systemic dissemination of Salmonella. While these processes are studied quite well in mice, the role of the NAIP/NLRC4 inflammasome in human IECs remains unknown. Unexpectedly, we found the NAIP/NLRC4 inflammasome is dispensable for early inflammasome responses to Salmonella in both human intestinal epithelial cell lines and organoids. Additionally, the NLRP3 inflammasome and the adaptor protein ASC are not required for inflammasome activation in Caco-2 cells. Instead, we observed a partial requirement for caspase-1, and a necessity for caspase-4 and GSDMD pore-forming activity in mediating inflammasome responses to Salmonella in Caco-2 cells. These findings suggest that unlike murine IECs, human IECs do not rely on NAIP/NLRC4, and also do not use NLRP3/ASC. Instead, they primarily use caspases-1 and -4 to mediate early inflammasome responses to SPI-1-expressing Salmonella.

microbiology↗

bioRxiv2021

The Card19 locus of murine chromosome 13 regulates terminal cell lysis downstream of caspase activation and Gasdermin-D cleavage

Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1{beta} release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during Yersinia infection, we identified a line of Card19-deficient mice (Card19lxcn) whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as two independently-generated CRISPR/Cas9 Card19 knockout mice showed no defect in macrophage cell lysis, and expression of CARD19 in Card19lxcn macrophages did not restore cell lysis. Card19 is located on chromosome 13, adjacent to Ninj1, which was recently reported to regulate cell lysis downstream of GSDMD activation. Intriguingly, RNA-seq and western blotting revealed that Card19lxcn BMDMs are hypomorphic for NINJ1 expression, and reconstitution of Ninj1 in Card19lxcn immortalized BMDMs restored cell lysis. Card19lxcn mice exhibited significantly increased susceptibility to Yersinia infection, demonstrating that cell lysis itself plays a key role in protection against bacterial infection. Our findings identify genetic targeting of Card19 being responsible for off-target effects on the adjacent Ninj1 gene, thereby disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during Yersinia infection. Author SummaryProgrammed cell death is critical for regulating tissue homeostasis and host defense against infection. Pyroptosis is an inflammatory form of programmed cell death that couples cell lysis with release of inflammatory cytokines. Cell lysis is triggered by activation of particular intracellular pore forming proteins, but how regulation of cell lysis occurs is not well understood. Genetic targeting of Card19 on chromosome 13 resulted in decreased expression of the adjacent gene, Ninj1 which was recently found to regulate terminal lysis events in response to cell death-inducing stimuli. We found that macrophages from Card19-deficient mice were resistant to multiple forms of cell death in response to a variety of inflammatory stimuli, including canonical and non-canonical inflammasome activation, as well as triggers of cell-extrinsic apoptosis. Notably, Card19-deficient mice were more susceptible to Yersinia infection, indicating that cell lysis contributes to control of bacterial infections. Our data provide new insight into the impact of terminal cell lysis on control of bacterial infection and highlight the role of additional factors that regulate lytic cell death downstream of gasdermin cleavage.

immunology↗