bims-inflin 2024-11-10 papers

on Inflammasome and infection

Issue of 2024–11–10
twelve papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto

C4b-Binding Protein and Factor H Inhibit Inflammasome Activation during Group A Streptococci Infection in Human Cells.
Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site.
Integrated Genetic and Cellular Analysis Reveals NLRP1 Activation in CD4+ T Lymphocytes During Chronic HIV Infection.
NLRP3 inflammasome activation contributes to acute liver injury caused by CVA6 infection in mice.
Non-tuberculous mycobacteria enhance the tryptophan-kynurenine pathway to induce immunosuppression and facilitate pulmonary colonization.
Pyroptotic executioner pore-forming protein GSDMD forms oligomeric assembly and exhibits amyloid-like attributes that could contribute for its pore-forming function.
Intestinal epithelial Gasdermin C is induced by IL-4R/STAT6 signaling but is dispensable for gut immune homeostasis.
Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases.
Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair.
Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.
Influenza A virus-induced glycolysis facilitates virus replication by activating ROS/HIF-1α pathway.
Pyroptosis regulation by Salmonella effectors.

J Innate Immun. 2024 Nov 04. 1-25

C4b-Binding Protein and Factor H Inhibit Inflammasome Activation during Group A Streptococci Infection in Human Cells.

Serena Bettoni, Mateusz Dziedzic, Damien Bierschenk, Maja Chrobak, Michal Magda, Maisem Laabei, Ben C King, Kristian Riesbeck, Anna M Blom.

INTRODUCTION: Streptococcus pyogenes (Group A Streptococcus; GAS) is a pathogen that causes over half a million deaths annually worldwide. Human immune cells respond to GAS infection by activating the NLRP3 inflammasome that leads to pro-inflammatory cytokines release which acts to control infection. We investigated the role of C4b-binding protein (C4BP) and Factor H (FH) in the inflammasome response to GAS, as they are recruited by GAS to prevent complement deposition and limit phagocytosis.
METHODS: Inflammasome response was investigated using isolated primary human cells and the GAS-AP1 strain. Cytokine responses were evaluated by ELISA. C4BP internalisation was investigated using confocal microscopy. Western blotting was used to evaluate the activation of NLRP3 inflammasome components.
RESULTS: IL-1β release, induced by GAS-AP1, was inhibited by FH which interferes with priming of human cells. In contrast, C4BP restricted the IL-1β response with no effect on cell priming. C4BP was engulfed by cells together with bacteria and excluded from low-pH vesicles, but localised within the cytosol and near the ASC speck inflammasome complex. C4BP did not inhibit either the inflammasome complex assembly or caspase-1 activation. However, C4BP limited the cleavage of gasderminD N-terminal fragments by interfering with caspase-1 enzymatic activity.
CONCLUSION: Our results provide new insights on the effect of FH and internalised C4BP to control GAS sensing by inflammasomes.

DOI: https://doi.org/10.1159/000542434
Front Immunol. 2024 ;15 1473133

Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site.

Olivia C Ihedioha, Haley Q Marcarian, Anutr Sivakoses, Stephen M Beverley, Diane McMahon-Pratt, Alfred L M Bothwell.

   Background: Host-related factors highly regulate the increased circulation of neutrophils during Leishmania infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during Leishmania infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases.
Results: In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6NKO) or BALB/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6NKO DKK1PKO). Relative to the infected wild-type BALB/c mice, reduced neutrophil activation at the infection site of LRP6NKO or LRP6NKO DKK1PKO mice was noted. The neutrophils obtained from either infected LRP6NKO or LRP6NKO DKK1PKO mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c mice, a significant reduction in parasite load was observed in both LRP6NKO and LRP6NKO DKK1PKO infected mice. Notably, DKK1 levels were comparable in the LRP6NKO and BALB/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in Leishmania disease. Thus, we further determine the contribution of Leishmania membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis (Δlpg1- ) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis (Δads1- ). Relative to the WT controls, Δads1- parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in Δlpg1- parasite-infected mice after day 3 PI.
Conclusion: Our results suggest that DKK1 signalling and Leishmania pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.

Keywords:  apoptosis; innate response; leishmaniasis; neutrophils; platelet

DOI:  https://doi.org/10.3389/fimmu.2024.1473133
Immunol Invest. 2024 Nov 04. 1-20

Integrated Genetic and Cellular Analysis Reveals NLRP1 Activation in CD4+ T Lymphocytes During Chronic HIV Infection.

Vinicius Nunes Cordeiro Leal, Mariela Estefany Gislane Vera Roa, Julia Silva Cantoni, Edione Cristina Dos Reis, Amanda Nazareth Lara, Alessandra Pontillo.

   BACKGROUND: Most of the investigations related to inflammasome activation during HIV infection have focused on the receptor NLRP3 and innate immune cells such as monocytes/macrophages. However, during the past years, inflammasome activation has also been explored in lymphocytes, and novel sensors, other than the NLRP3, have been shown to play a role in the biology of these cells. Here, we hypothesized that NLRP1 may be involved in CD4+ T cell dysregulation in people living with HIV (PLWH), therefore contributing to chronic inflammation and to the pathogenesis of non-HIV-associated diseases.
METHODS: The activation of NLRP1 in CD4+ T cells was assessed ex-vivo and in-vitro by the meaning of anti-CD3/anti-CD28 and Talabostat/Val-boroPro (VbP) response.
RESULTS: Our results showed that the NLRP1 inflammasome was activated in PLWH CD4+ T cells, and that the stimulation of CD4+ T cells resulted in increased response to anti-CD3/anti-CD28 and VbP. Functional variants in NLRP1 significantly affected the level of inflammatory dysregulation of CD4+ T cells, therefore explaining at least in part the association with CD4+ T-mediated diseases.
CONCLUSION: PLWH CD4+ T cells are more prone to IL-1β release and pyroptosis, therefore contributing to chronic inflammation.

Keywords:  Chronic infection; HIV-1; NLRP1; SNVs; genetic; inflammasome

DOI:  https://doi.org/10.1080/08820139.2024.2419940
BMC Infect Dis. 2024 Nov 05. 24(1): 1251

NLRP3 inflammasome activation contributes to acute liver injury caused by CVA6 infection in mice.

Yaqi Xie, Quanman Hu, Guangcai Duan, Fang Wang, Feifei Feng, Dong Li, Wenjie Jiang, Wangquan Ji, Peiyu Zhu, Xiaolong Zhang, Jinzhao Long, Huifen Feng, Haiyan Yang, Shuaiyin Chen, Yuefei Jin.

   BACKGROUND: Coxsackievirus (CV) A6 has emerged as an important causative agent in global outbreaks of hand, foot, and mouth disease (HFMD), which typically presents as a mild illness with a large generalized rash, herpes. However, some patients can develop encephalitis, pneumonia, myocarditis and liver injury. Our previous study took the view that CVA6 could replicate in mouse liver, leading to acute liver injury; however, the precise underlying mechanism remains elusive.
METHODS: 10-day-old wild-type (WT, C57BL/6J) and NLRP3 knock-out (KO) mice were intraperitoneal (i.p.) inoculated with a lethal dose of the CVA6 strain. The muscle homogenate supernatant from normal mice was used to inoculate mock-infected mice. At 5 days post infection (dpi), the mouse liver was taken out for histopathological analyses and molecular biology experiments.
RESULTS: Our in vivo experiments demonstrated that CVA6 caused severe liver injury in mice, as evidenced by pathological changes in liver slices, elevated liver injury markers (e.g., AST, ALT, LDH) and pro-inflammatory cytokines (e.g., IL-6, MCP-1, TNF-α, IL-1β). Further results revealed the activation of NLRP3 inflammasome characterized by the increase in the expression of NLRP3, Cleaved-Casp-1 (p20), mature IL-1β and IL-18. Importantly, upon CVA6 infection, NLRP3 KO mice exhibited attenuated pathological damage and reduced levels of pro-inflammatory cytokines production (e.g., TNF-α and IL-1β) compared with WT mice. Finally, increased levels of blood ALT, AST, LDH were strongly correlated with the severity of CVA6 patients.
CONCLUSION: Collectively, our findings suggest that the activation of NLRP3 inflammasome is involved in CVA6 infection-induced acute liver injury, providing novel insights into CVA6 infection associated adverse clinical outcomes.

Keywords:  CVA6; HFMD; Liver injury; NLRP3

DOI:  https://doi.org/10.1186/s12879-024-10136-2
Front Cell Infect Microbiol. 2024 ;14 1455605

Non-tuberculous mycobacteria enhance the tryptophan-kynurenine pathway to induce immunosuppression and facilitate pulmonary colonization.

Longjie Li, Jiaofang Shao, Chunran Tong, Weiwei Gao, Pan Pan, Chen Qi, Chenxi Gao, Yunlei Zhang, Ying Zhu, Cheng Chen.

  The increasing prevalence of non-tuberculous mycobacterium (NTM) infections alongside tuberculosis (TB) underscores a pressing public health challenge. Yet, the mechanisms governing their infection within the lung remain poorly understood. Here, we integrate metagenomic sequencing, metabolomic sequencing, machine learning classifiers, SparCC, and MetOrigin methods to profile bronchoalveolar lavage fluid (BALF) samples from NTM/TB patients. Our aim is to unravel the intricate interplay between lung microbial communities and NTM/Mycobacterium tuberculosis infections. Our investigation reveals a discernible reduction in the compositional diversity of the lung microbiota and a diminished degree of mutual interaction concomitant with NTM/TB infections. Notably, NTM patients exhibit a distinct microbial community characterized by marked specialization and notable enrichment of Pseudomonas aeruginosa and Staphylococcus aureus, driving pronounced niche specialization for NTM infection. Simultaneously, these microbial shifts significantly disrupt tryptophan metabolism in NTM infection, leading to an elevation of kynurenine. Mycobacterium intracellulare, Mycobacterium paraintracellulare, Mycobacterium abscessus, and Pseudomonas aeruginosa have been implicated in the metabolic pathways associated with the conversion of indole to tryptophan via tryptophan synthase within NTM patients. Additionally, indoleamine-2,3-dioxygenase converts tryptophan into kynurenine, fostering an immunosuppressive milieu during NTM infection. This strategic modulation supports microbial persistence, enabling evasion from immune surveillance and perpetuating a protracted state of NTM infection. The elucidation of these nuanced microbial and metabolic dynamics provides a profound understanding of the intricate processes underlying NTM and TB infections, offering potential avenues for therapeutic intervention and management.

Keywords:  bronchoalveolar lavage fluid; immunosuppressive milieu; lung microbiota; microbial interaction; non-tuberculous mycobacterium; tuberculosis

DOI:  https://doi.org/10.3389/fcimb.2024.1455605
Biochem J. 2024 Nov 06. pii: BCJ20240416. [Epub ahead of print]

Pyroptotic executioner pore-forming protein GSDMD forms oligomeric assembly and exhibits amyloid-like attributes that could contribute for its pore-forming function.

Shamaita Chatterjee, Tarang Gupta, Gurvinder Kaur, Kausik Chattopadhyay.

  Gasdermin D (GSDMD) is the chief executioner of inflammatory cell death or pyroptosis. During pyroptosis, proteolytic processing of GSDMD releases its N-terminal domain (NTD), which then forms large oligomeric pores in the plasma membranes. Membrane pore-formation by NTD allows the release of inflammatory cytokines and causes membrane damage to induce cell death. Structural mechanisms of GSDMD-mediated membrane pore-formation have been extensively studied. However, less effort has been made to understand the physicochemical properties of GSDMD and their functional implications. Here, we explore detailed characterization of the physicochemical properties of mouse GSDMD (mGSDMD), and their implications in regulating the pore-forming function. Our study reveals that mGSDMD shows some of the hallmark features of amyloids, and forms oligomeric assemblies in solution that are critically dependent on the disulphide bond-forming ability of the protein. mGSDMD oligomeric assemblies do not resemble typical amyloid fibrils/aggregates, and do not show resistance to proteolytic degradation that is otherwise observed with the conventional amyloids. Our results further elucidate the essential role of an amyloid-prone region (APR) in the oligomerization and amyloid-like features of mGSDMD. Furthermore, alteration of this APR leads to compromised pore-forming ability and cell-killing activity of NTD released from mGSDMD. Taken together, our study for the first time provides crucial new insights regarding implications of the amyloid-like property of mGSDMD in regulating its pore-forming function, which is an essential requirement for this pyroptotic executioner. To the best of our knowledge, such mode of regulation of mGSDMD-function has not been appreciated so far.

Keywords:  Gasdermin D; amyloid; cell death; oligomerization; pore-forming protein; pyroptosis

DOI:  https://doi.org/10.1042/BCJ20240416
Sci Rep. 2024 11 03. 14(1): 26522

Intestinal epithelial Gasdermin C is induced by IL-4R/STAT6 signaling but is dispensable for gut immune homeostasis.

Reyes Gámez-Belmonte, Yara Wagner, Mousumi Mahapatro, Ru Wang, Lena Erkert, Miguel González-Acera, Roodline Cineus, Saskia Hainbuch, Jay V Patankar, David Voehringer, Ahmed N Hegazy, Markus F Neurath, Stefan Wirtz, Christoph Becker.

  Gasdermin C is one of the least studied members of the gasdermin family of proteins, known for their critical involvement in pyroptosis and host defense. Furthermore, evidence for the role of Gasdermin C in the intestine is scarce and partly controversial. Here, we tested the functional role of Gasdermin C in intestinal homeostasis, inflammation and tumorigenesis. : We studied Gasdermin C in response to cytokines in intestinal organoids. We evaluated epithelial differentiation, cell death and immune infiltration under steady state conditions in a new mouse line deficient in Gasdermin C. The role of Gasdermin C was analyzed in acute colitis, infection and colitis-associated cancer. Gasdemin C is highly expressed in the intestinal epithelium and strongly induced by the type 2 cytokines IL-4 and IL-13 in a STAT6-dependent manner. Gasdermin C-deficient mice show no changes in tissue architecture and epithelial homeostasis. Epithelial organoids deficient in Gasdermin C develop normally and show no alterations in proliferation or cell death. No changes were found in models of acute colitis, type 2 intestinal infection and colitis-associated cancer. Gasdermin C genes are upregulated by type 2 immunity, yet appear dispensable for the development of intestinal inflammation, infection and colitis-associated cancer.

Keywords:  Gasdermin; Gut pathology; Intestinal homeostasis

DOI:  https://doi.org/10.1038/s41598-024-78336-z
Cell Immunol. 2024 Oct 26. pii: S0008-8749(24)00091-1. [Epub ahead of print]405-406 104888

Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases.

Peipei Chen, Yunshu Wang, Huaiping Tang, Zhuo Liu, Jing Wang, Tingting Wang, Yun Xu, Sen-Lin Ji.

  Pyroptosis, a form of inflammatory programmed cell death, plays a pivotal role in the pathogenesis of various diseases. This process is primarily mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3). Gastrodenol (Bismuth tripotassium dicitrate, GAS) is a mineral compound which is used to treat duodenal and gastric ulcers associated with Helicobacter pylori. In this study, GAS was found to exhibit protective effects against classical pyroptosis in macrophages. Specifically, GAS effectively inhibits the activation of the NLRP3 inflammasome, Gasdermin D (GSDMD)-mediated pyroptosis, and the secretion of pro-inflammatory cytokines. Mechanistically, GAS inhibited NLRP3 oligomerization and reduced the oligomerization of adaptor protein apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC) by directly binding to NLRP3. The interaction between GAS and NLRP3 is primarily mediated through hydrogen bonding and hydrophobic forces. Hydrogen bonds are formed with PHE-727, LEU-723, and ASP-700. Remarkably, GAS treatment attenuated pyroptosis-mediated inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), lipopolysaccharide (LPS)-induced septic, and monosodium urate (MSU)-induced peritonitis in mice. To conclude, this is the first report that discovered clinical old medicine GAS as a potent inhibitor of pyroptosis and propose a novel therapeutic strategy for the prevention and treatment of NLRP3-GSDMD mediated diseases.

Keywords:  Experimental autoimmune encephalomyelitis; Gastrodenol; NLRP3 inflammasome; Pyroptosis; Sepsis

DOI:  https://doi.org/10.1016/j.cellimm.2024.104888
Cell. 2024 Oct 30. pii: S0092-8674(24)01158-9. [Epub ahead of print]

Type III interferons induce pyroptosis in gut epithelial cells and impair mucosal repair.

Kautilya K Jena, Julien Mambu, Daniel Boehmer, Benedetta Sposito, Virginie Millet, Joshua de Sousa Casal, Hayley I Muendlein, Roberto Spreafico, Romain Fenouil, Lionel Spinelli, Sarah Wurbel, Chloé Riquier, Franck Galland, Philippe Naquet, Lionel Chasson, Megan Elkins, Vanessa Mitsialis, Natália Ketelut-Carneiro, Katlynn Bugda Gwilt, Jay R Thiagarajah, Hai-Bin Ruan, Zhaoyu Lin, Egil Lien, Feng Shao, Janet Chou, Alexander Poltorak, Jose Ordovas-Montanes, Katherine A Fitzgerald, Scott B Snapper, Achille Broggi, Ivan Zanoni.

  Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight into how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or type II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to caspase-8 activation and the cleavage of gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has implications for IBD patients or individuals exposed to radiation therapies.

Keywords:  Z-nucleic acid; colitis; damage; gasdermin; inflammation; inflammatory bowel disease; interferons; intestinal epithelial cell; intestinal stem cell; irradiation; pattern recognition receptors; pyroptosis; repair

DOI:  https://doi.org/10.1016/j.cell.2024.10.010
Eur J Immunol. 2024 Nov 05. e2350378

Alveolar epithelial cells shape lipopolysaccharide-induced inflammatory responses and reprogramming of alveolar macrophages.

Wei Jiang, Yeying Chen, Cheng-Yun Yu, Benkun Zou, Yimeng Lu, Qian Yang, Zihui Tang, Weiying Mao, Jing Li, Han Han, Lingyun Shao, Jiashun Zeng, Yiwei Chu, Jianguo Tang, Mingfang Lu.

  Alveolar macrophages (AMs) are sentinels in the airways, where they sense and respond to invading microbes and other stimuli. Unlike macrophages in other locations, AMs can remain responsive to Gram-negative lipopolysaccharides (LPS) after they have responded to LPS in vivo (they do not develop "endotoxin tolerance"), suggesting that the alveolar microenvironment may influence their responses. Although alveolar epithelial cells (AECs) normally limit AMs' innate responses, preventing inflammation induced by harmless antigens in the lung, how AECs influence the innate responses of AMs to infectious agents has been uncertain. Here we report that (1) after exposure to aspirated (intranasal instillation) LPS, AMs increase their responses to TLR agonists and elevate their phagocytic and bactericidal activities in mice; (2) Aspirated LPS pre-exposure increases host resistance to pulmonary infection caused by Gram-negative bacteria and the protection effect lasts for at least 35 days; (3) LPS stimulation of AECs both increases AMs' innate immune responses and prevents AMs from developing tolerance in vitro; (4) Upon LPS stimulation, AMs secreted TNF-α induces AECs to release GM-CSF, which potentiates AMs' response. These experiments have revealed a previously unappreciated role that AECs may play in boosting the innate responses of AMs and promoting resistance to pulmonary infections.

Keywords:  Alveolar epithelial cells (AECs); Alveolar macrophages (AMs); Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF); Macrophage reprogramming

DOI:  https://doi.org/10.1002/eji.202350378
Free Radic Biol Med. 2024 Nov 02. pii: S0891-5849(24)01012-8. [Epub ahead of print]

Influenza A virus-induced glycolysis facilitates virus replication by activating ROS/HIF-1α pathway.

Yijia Zhang, Lifeng Chang, Xin Xin, Yixuan Qiao, Wenna Qiao, Jihui Ping, Jun Xia, Juan Su.

  As a highly contagious acute respiratory disease, influenza A virus (A/WSN/1933) poses a huge threat to human health and public health. influenza A virus proliferation relies on glucose metabolism in host cells, yet the effects of influenza A virus on glucose metabolism and the underlying molecular mechanisms remain unclear. Here, we created models of WSN virus-infected mice and A549 cells, along with analyzing metabolomics and transcriptomics data, to investigate how WSN virus infection affects host cell glucose metabolism and specific mechanisms. Analysis of metabolites and gene expression showed that WSN virus infection triggers glycolysis in A549 cells, with notable upregulation of hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), hypoxia-inducible factor-1 alpha (HIF-1α), and elevated lactate levels. Additionally, it leads to mitochondrial impairment and heightened reactive oxygen species (ROS) generation. Elevated levels of glucose may enhance the replication of WSN virus, whereas inhibitors of glycolysis can reduce it. Enhancement of HIF-1α activation facilitated replication of WSN virus through stimulation of lactate synthesis, with the primary influence of glycolysis on WSN virus replication being mediated by ROS/HIF-1α signaling. Mice given HIF-1α inhibitor PTX-478 or glycolysis inhibitor 2-Deoxyglucose (2-DG) exhibited reduced lactate levels and decreased WSN virus replication, along with mitigated weight loss and lung damage. In summary, WSN virus-induced glycolysis has been demonstrated to enhance virus replication through the activation of the ROS/HIF-1α pathway, suggesting potential new targets for combating the virus.

Keywords:  HIF-1α; Influenza A virus; ROS; glycolysis; lung; mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.304
Front Immunol. 2024 ;15 1464858

Pyroptosis regulation by Salmonella effectors.

Yuan Meng, Qianjin Zhang, Mengen Xu, Ke Ding, Zuhua Yu, Jing Li.

  The genus Salmonella contains the most common foodborne pathogens frequently isolated from food-producing animals and is responsible for zoonotic infections in humans and animals. Salmonella infection in humans and animals can cause intestinal damage, resulting in intestinal inflammation and disruption of intestinal homeostasis more severe cases can lead to bacteremia. Pyroptosis, a proinflammatory form of programmed cell death, is involved in many disease processes. Inflammasomes, pyroptosis, along with their respective signaling cascades, are instrumental in the preservation of intestinal homeostasis. In recent years, with the in-depth study of pyroptosis, our comprehension of the virulence factors and effector proteins in Salmonella has reached an extensive level, a deficit persists in our knowledge regarding the intrinsic pathogenic mechanisms about pyroptosis, necessitating a continued pursuit of understanding and investigation. In this review, we discuss the occurrence of pyroptosis induced by Salmonella effectors to provide new ideas for elucidating the regulatory mechanisms through which Salmonella virulence factors and effector proteins trigger pyroptosis could pave the way for novel concepts and strategies in the clinical prevention of Salmonella infections and the treatment of associated diseases.

Keywords:  Salmonella; effector protein; inflammasome; pyroptosis; virulence factors

DOI:  https://doi.org/10.3389/fimmu.2024.1464858