Oxidative metabolism enables <i>Salmonella</i> evasion of the NLRP3 inflammasome

Wynosky-Dolfi, Meghan A.; Snyder, Annelise G.; Philip, Naomi H.; Doonan, Patrick J.; Poffenberger, Maya C.; Avizonis, Daina; Zwack, Erin E.; Riblett, Amber M.; Hu, Baofeng; Strowig, Till; Flavell, Richard A.; Jones, Russell G.; Freedman, Bruce D.; Brodsky, Igor E.

doi:10.1084/jem.20130627

Cited by 84 publications

(76 citation statements)

References 109 publications

(184 reference statements)

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“…4D). Consistent with our findings, a recent study reported that the NLRP3 inflammasome was activated by the mitochondrial superoxide induced during S. Typhimurium infection of BMDMs (50). Under curliinducing conditions, the flagellin mutant did not have a profound effect on IL-1␤ production (Fig.…”

Section: Discussionsupporting

confidence: 92%

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

et al. 2015

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bAmyloids are proteins with cross-␤-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1␤ (IL-1␤). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced by Salmonella enterica serovar Typhimurium and Escherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1␤ via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1␤. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid ␤ of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1␤ as a product of this interaction.A myloid proteins are produced by both bacteria and humans. In humans, more than 60 amyloidogenic proteins are produced throughout the body (1). Amyloids accumulate, forming deposits, during several complex diseases, such as Alzheimer's disease (AD), Parkinson's disease, type II diabetes, and secondary amyloidosis. Although it was initially thought that amyloids were only misfolded proteins causing disease pathology, it is becoming more apparent that the proteins have a function in the human body (2, 3). For instance, Pmel17, involved in melanin production, prevents melanocyte cytotoxicity (4-6), and secretory hormones in the endocrine system are stored in a cross-beta-sheetrich structure in secretory granules (7). Furthermore, it has recently been proposed that the amyloid ␤ peptide, found in the senile plaques of Alzheimer's disease patients, binds specific DNA regions and participates in gene regulation (8).Bacteria produce amyloids as a component of their extracellular matrix (ECM) to build multicellular communities termed biofilms (9). Biofilms are characterized by their resistant nature in response to environmental insults, including chemical treatments, antibiotics, and the immune system (10). It is thought that the amyloids act as a shield to protect bacteria in biofilms due to their highly resistant nature against chemicals and proteolytic enzymes. Although it is estimated that up to 40% of bacterial species produce amyloids in their biofilms (11), most of these proteins remain uncharacterized. Curli fibers, amyloids produced in the biofilms of Escherichia coli and Salmonella enterica serovar Typhimurium, are the most studied bacterial amyloid to date. Curli fibers are encoded by the csg gene cluster formed by two operons, csgBAC and csgDEFG (12-14). CsgA, the ...

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Section: Discussionsupporting

confidence: 92%

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

et al. 2015

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“…It is likely that during Salmonella infection, multiple receptors are engaged in tandem, generating a mixed response that is evident in the in vivo mouse models. In addition, Salmonella that lacks aconitase has attenuated virulence that is dependent on rapid NLRP3 inflammasome activation [81]. Neutrophils can also activate the NLRC4 inflammasome in response to Salmonella infection and make IL-1β but do not undergo pyroptosis (in contrast to macrophages) leading to sustained IL-1β production [82].…”

Section: Pathogens Differentially Interfere With the Inflammasomes Anmentioning

confidence: 99%

Checks and Balances between Autophagy and Inflammasomes during Infection

Seveau

Turner

Gavrilin

et al. 2018

Journal of Molecular Biology

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Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the serine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.

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“…S. typhimurium has also developed mechanisms to evade NLRP3 inflammasome activation by utilizing the TCA enzymes aconitase (acnB) and isocitrate dehydrogenase (icdA). Interestingly, acnB and icdA mutants induced rapid NLRP3 inflammasome activation through a process that resulted in elevated bacterial citrate and increased mitochondrial reactive oxygen species (34).…”

Section: Bacterial Effector Molecules That Facilitate Evasion Of Inflmentioning

confidence: 99%

Evasion of inflammasome activation by microbial pathogens

Ulland¹,

Ferguson²,

Sutterwala³

2015

J. Clin. Invest.

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Oxidative metabolism enables Salmonella evasion of the NLRP3 inflammasome

Abstract: Salmonella lacking the TCA enzyme aconitase trigger NLRP3 inflammasome activation in infected macrophages, leading to elevated inflammatory responses and reduced virulence.

Cited by 84 publications

References 109 publications

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

Checks and Balances between Autophagy and Inflammasomes during Infection

Evasion of inflammasome activation by microbial pathogens

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