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Article ; Online: Epithelial inflammasomes, gasdermins, and mucosal inflammation - Lessons from Salmonella and Shigella infected mice.

Gül, Ersin / Fattinger, Stefan A / Sellin, Mikael E / Hardt, Wolf-Dietrich

2023 Volume 70, Page(s) 101812

Abstract: ... executed in the absence of GSDMD. In fact, several reports highlighted that various cell death pathways (e ...

Abstract	Besides its crucial function in nutrient absorbance and as barrier against the microbiota, the gut epithelium is essential for sensing pathogenic insults and mounting of an appropriate early immune response. In mice, the activation of the canonical NAIP/NLRC4 inflammasome is critical for the defense against enterobacterial infections. Activation of the NAIP/NLRC4 inflammasome triggers the extrusion of infected intestinal epithelial cells (IEC) into the gut lumen, concomitant with inflammasome-mediated lytic cell death. The membrane permeabilization, a hallmark of pyroptosis, is caused by the pore-forming proteins called gasdermins (GSDMs). Recent work has revealed that NAIP/NLRC4-dependent extrusion of infected IECs can, however, also be executed in the absence of GSDMD. In fact, several reports highlighted that various cell death pathways (e.g., pyroptosis or apoptosis) and unique mechanisms specific to particular infection models and stages of gut infection are in action during epithelial inflammasome defense against intestinal pathogens. Here, we summarize the current knowledge regarding the underlying mechanisms and speculate on the putative functions of the epithelial inflammasome activation and cell death, with a particular emphasis on mouse infection models for two prominent enterobacterial pathogens, Salmonella Typhimurium and Shigella flexneri.
MeSH term(s)	Mice ; Animals ; Humans ; Inflammasomes ; Gasdermins ; Salmonella typhimurium/metabolism ; Shigella/metabolism ; Inflammation
Chemical Substances	Inflammasomes ; Gasdermins
Language	English
Publishing date	2023-08-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2023.101812
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Article ; Online: Salmonella effector driven invasion of the gut epithelium: breaking in and setting the house on fire.

Fattinger, Stefan A / Sellin, Mikael E / Hardt, Wolf-Dietrich

Current opinion in microbiology

2021 Volume 64, Page(s) 9–18

Abstract: ... tissue culture cells, the TTSS-1 effectors (mainly SopB/E/E2) elicit large membrane ruffles fueling cooperative ...

Abstract	Salmonella Typhimurium (S.Tm) is a major cause of diarrheal disease. The invasion into intestinal epithelial cells (IECs) is a central step in the infection cycle. It is associated with gut inflammation and thought to benefit S.Tm proliferation also in the intestinal lumen. Importantly, it is still not entirely clear how inflammation is elicited and to which extent it links to IEC invasion efficiency in vivo. In this review, we summarize recent findings explaining IEC invasion by type-three-secretion-system-1 (TTSS-1) effector proteins and discuss their effects on invasion and gut inflammation. In non-polarized tissue culture cells, the TTSS-1 effectors (mainly SopB/E/E2) elicit large membrane ruffles fueling cooperative invasion, and can directly trigger pro-inflammatory signaling. By contrast, in the murine gut, we observe discreet-invasion (mainly via the TTSS-1 effector SipA) and a prominent pro-inflammatory role of the host?"s epithelial inflammasome(s), which sense pathogen associated molecular patterns (PAMPs). We discuss why it has remained a major challenge to tease apart direct and indirect inflammatory effects of TTSS-1 effectors and explain why further research will be needed to fully determine their inflammation-modulating role(s).
MeSH term(s)	Animals ; Bacterial Proteins/genetics ; Epithelial Cells ; Epithelium ; Mice ; Salmonella typhimurium/genetics ; Type III Secretion Systems
Chemical Substances	Bacterial Proteins ; Type III Secretion Systems
Language	English
Publishing date	2021-09-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2021.08.007
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Article ; Online: Epithelial inflammasomes in the defense against Salmonella gut infection.

Fattinger, Stefan A / Sellin, Mikael E / Hardt, Wolf-Dietrich

Current opinion in microbiology

2020 Volume 59, Page(s) 86–94

Abstract: The gut epithelium prevents bacterial access to the host's tissues and coordinates a number of mucosal defenses. Here, we review the function of epithelial inflammasomes in the infected host and focus on their role in defense against Salmonella ... ...

Abstract	The gut epithelium prevents bacterial access to the host's tissues and coordinates a number of mucosal defenses. Here, we review the function of epithelial inflammasomes in the infected host and focus on their role in defense against Salmonella Typhimurium. This pathogen employs flagella to swim towards the epithelium and a type III secretion system (TTSS) to dock and invade intestinal epithelial cells. Flagella and TTSS components are recognized by the canonical NAIP/NLRC4 inflammasome, while LPS activates the non-canonical Caspase-4/11 inflammasome. The relative contributions of these inflammasomes, the activated cell death pathways and the elicited mucosal defenses are subject to environmental control and appear to change along the infection trajectory. It will be an important future task to explain how this may enable defense against the challenges imposed by diverse bacterial enteropathogens.
MeSH term(s)	Humans ; Inflammasomes/immunology ; Salmonella Infections/immunology ; Salmonella typhimurium
Chemical Substances	Inflammasomes
Language	English
Publishing date	2020-10-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2020.09.014
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Article ; Online: Direct Salmonella injection into enteroid cells allows the study of host-pathogen interactions in the cytosol with high spatiotemporal resolution.

Ernst, Chantal / Andreassen, Patrick R / Giger, Gabriel H / Nguyen, Bidong D / Gäbelein, Christoph G / Guillaume-Gentil, Orane / Fattinger, Stefan A / Sellin, Mikael E / Hardt, Wolf-Dietrich / Vorholt, Julia A

PLoS biology

2024 Volume 22, Issue 4, Page(s) e3002597

Abstract: ... results in rapid host cell responses, i.e., the activation of inflammasomes. Here, we introduce a single ...

Abstract	Intestinal epithelial cells (IECs) play pivotal roles in nutrient uptake and in the protection against gut microorganisms. However, certain enteric pathogens, such as Salmonella enterica serovar Typhimurium (S. Tm), can invade IECs by employing flagella and type III secretion systems (T3SSs) with cognate effector proteins and exploit IECs as a replicative niche. Detection of flagella or T3SS proteins by IECs results in rapid host cell responses, i.e., the activation of inflammasomes. Here, we introduce a single-cell manipulation technology based on fluidic force microscopy (FluidFM) that enables direct bacteria delivery into the cytosol of single IECs within a murine enteroid monolayer. This approach allows to specifically study pathogen-host cell interactions in the cytosol uncoupled from preceding events such as docking, initiation of uptake, or vacuole escape. Consistent with current understanding, we show using a live-cell inflammasome reporter that exposure of the IEC cytosol to S. Tm induces NAIP/NLRC4 inflammasomes via its known ligands flagellin and T3SS rod and needle. Injected S. Tm mutants devoid of these invasion-relevant ligands were able to grow in the cytosol of IECs despite the absence of T3SS functions, suggesting that, in the absence of NAIP/NLRC4 inflammasome activation and the ensuing cell death, no effector-mediated host cell manipulation is required to render the epithelial cytosol growth-permissive for S. Tm. Overall, the experimental system to introduce S. Tm into single enteroid cells enables investigations into the molecular basis governing host-pathogen interactions in the cytosol with high spatiotemporal resolution.
MeSH term(s)	Cytosol/metabolism ; Cytosol/microbiology ; Animals ; Salmonella typhimurium/pathogenicity ; Salmonella typhimurium/metabolism ; Host-Pathogen Interactions ; Type III Secretion Systems/metabolism ; Inflammasomes/metabolism ; Mice ; Flagellin/metabolism ; Neuronal Apoptosis-Inhibitory Protein/metabolism ; Neuronal Apoptosis-Inhibitory Protein/genetics ; Epithelial Cells/microbiology ; Epithelial Cells/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Apoptosis Regulatory Proteins/genetics ; Mice, Inbred C57BL ; CARD Signaling Adaptor Proteins/metabolism ; CARD Signaling Adaptor Proteins/genetics ; Single-Cell Analysis/methods ; Salmonella Infections/microbiology ; Salmonella Infections/metabolism ; Salmonella Infections/immunology ; Intestinal Mucosa/microbiology ; Intestinal Mucosa/metabolism ; Calcium-Binding Proteins
Chemical Substances	Type III Secretion Systems ; Inflammasomes ; Flagellin (12777-81-0) ; Neuronal Apoptosis-Inhibitory Protein ; Apoptosis Regulatory Proteins ; Ipaf protein, mouse ; CARD Signaling Adaptor Proteins ; Calcium-Binding Proteins
Language	English
Publishing date	2024-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3002597
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Article ; Online: A motile doublet form of Salmonella Typhimurium diversifies target search behavior at the epithelial surface.

Ek, Viktor / Fattinger, Stefan A / Florbrant, Alexandra / Hardt, Wolf-Dietrich / Di Martino, Maria Letizia / Eriksson, Jens / Sellin, Mikael E

Molecular microbiology

2022 Volume 117, Issue 5, Page(s) 1156–1172

Abstract: The behaviors of infectious bacteria are commonly studied in bulk. This is effective to define the general properties of a given isolate, but insufficient to resolve subpopulations and unique single-microbe behaviors within the bacterial pool. We here ... ...

Abstract	The behaviors of infectious bacteria are commonly studied in bulk. This is effective to define the general properties of a given isolate, but insufficient to resolve subpopulations and unique single-microbe behaviors within the bacterial pool. We here employ microscopy to study single-bacterium characteristics among Salmonella enterica serovar Typhimurium (S.Tm), as they prepare for and launch invasion of epithelial host cells. We find that during the bacterial growth cycle, S.Tm populations switch gradually from fast planktonic growth to a host cell-invasive phenotype, characterized by flagellar motility and expression of the Type-three-secretion-system-1. The indistinct nature of this shift leads to the establishment of a transient subpopulation of S.Tm "doublets"-waist-bearing bacteria anticipating cell division-which simultaneously express host cell invasion machinery. In epithelial cell culture infections, these S.Tm doublets outperform their "singlet" brethren and represent a hyperinvasive subpopulation. Atop both glass and enteroid-derived monolayers, doublets swim along markedly straighter trajectories than singlets, thereby diversifying search patterns and improving the surface exploration capacity of the total bacterial population. The straighter swimming, combined with an enhanced cell-adhesion propensity, suffices to account for the hyperinvasive doublet phenotype. This work highlights bacterial cell length heterogeneity as a key determinant of target search patterns atop epithelia.
MeSH term(s)	Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Epithelial Cells/microbiology ; Phenotype ; Salmonella typhimurium/metabolism ; Serogroup ; Type III Secretion Systems/metabolism
Chemical Substances	Bacterial Proteins ; Type III Secretion Systems
Language	English
Publishing date	2022-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.14898
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Article ; Online: Does change of responsibility reduce escalating commitment? A replication and theoretical extension.

Schultze, Thomas / Schulz-Hardt, Stefan

Journal of experimental psychology. Applied

2021 Volume 28, Issue 1, Page(s) 189–204

Abstract: ... escalating commitment (i.e., the failure to withdraw from losing courses of action). This intervention is ...

Abstract	Reassigning responsibility is the most prominent and best-replicated intervention against escalating commitment (i.e., the failure to withdraw from losing courses of action). This intervention is considered effective because it reduces reinvestments after negative feedback in decision scenarios with a single reinvestment decision. However, we argue that any intervention against escalating commitment should fulfill two additional criteria. The first is temporal stability, that is, the beneficial effects of the intervention need to persist beyond a single reinvestment decision. The second is specific effectiveness, that is, the intervention should reduce commitment only if the project continues to fail after an initial setback (structural failure) but not if it recovers and is ultimately profitable (temporary failure). To subject reassignment of responsibility to this critical test of effectiveness, we introduce a modification of the escalation paradigm that allows testing for temporal stability and differentiates between structural and temporary failure. In the first of two experiments, we did not find evidence of temporal stability. Experiment 2 found persistent short-term effects of responsibility reassignment, but these effects were unspecific, reducing commitment to both losing and ultimately successful courses of action. Our findings question the usefulness of responsibility reassignment as an effective intervention against escalating commitment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
MeSH term(s)	Feedback ; Humans ; Social Behavior
Language	English
Publishing date	2021-06-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2103149-6
ISSN	1939-2192 ; 1076-898X
ISSN (online)	1939-2192
ISSN	1076-898X
DOI	10.1037/xap0000366
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Article ; Online: Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells during Salmonella gut infection.

Gül, Ersin / Enz, Ursina / Maurer, Luca / Abi Younes, Andrew / Fattinger, Stefan A / Nguyen, Bidong D / Hausmann, Annika / Furter, Markus / Barthel, Manja / Sellin, Mikael E / Hardt, Wolf-Dietrich

PLoS pathogens

2023 Volume 19, Issue 6, Page(s) e1011235

Abstract: Recruitment of neutrophils into and across the gut mucosa is a cardinal feature of intestinal inflammation in response to enteric infections. Previous work using the model pathogen Salmonella enterica serovar Typhimurium (S.Tm) established that invasion ... ...

Abstract	Recruitment of neutrophils into and across the gut mucosa is a cardinal feature of intestinal inflammation in response to enteric infections. Previous work using the model pathogen Salmonella enterica serovar Typhimurium (S.Tm) established that invasion of intestinal epithelial cells by S.Tm leads to recruitment of neutrophils into the gut lumen, where they can reduce pathogen loads transiently. Notably, a fraction of the pathogen population can survive this defense, re-grow to high density, and continue triggering enteropathy. However, the functions of intraluminal neutrophils in the defense against enteric pathogens and their effects on preventing or aggravating epithelial damage are still not fully understood. Here, we address this question via neutrophil depletion in different mouse models of Salmonella colitis, which differ in their degree of enteropathy. In an antibiotic pretreated mouse model, neutrophil depletion by an anti-Ly6G antibody exacerbated epithelial damage. This could be linked to compromised neutrophil-mediated elimination and reduced physical blocking of the gut-luminal S.Tm population, such that the pathogen density remained high near the epithelial surface throughout the infection. Control infections with a ssaV mutant and gentamicin-mediated elimination of gut-luminal pathogens further supported that neutrophils are protecting the luminal surface of the gut epithelium. Neutrophil depletion in germ-free and gnotobiotic mice hinted that the microbiota can modulate the infection kinetics and ameliorate epithelium-disruptive enteropathy even in the absence of neutrophil-protection. Together, our data indicate that the well-known protective effect of the microbiota is augmented by intraluminal neutrophils. After antibiotic-mediated microbiota disruption, neutrophils are central for maintaining epithelial barrier integrity during acute Salmonella-induced gut inflammation, by limiting the sustained pathogen assault on the epithelium in a critical window of the infection.
MeSH term(s)	Animals ; Mice ; Neutrophils ; Salmonella Infections ; Salmonella typhimurium ; Epithelial Cells ; Anti-Bacterial Agents ; Inflammation ; Epithelium ; Intestinal Mucosa
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011235
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Article ; Online: Gasdermin D is the only Gasdermin that provides protection against acute

Fattinger, Stefan A / Maurer, Luca / Geiser, Petra / Bernard, Elliott M / Enz, Ursina / Ganguillet, Suwannee / Gül, Ersin / Kroon, Sanne / Demarco, Benjamin / Mack, Vanessa / Furter, Markus / Barthel, Manja / Pelczar, Pawel / Shao, Feng / Broz, Petr / Sellin, Mikael E / Hardt, Wolf-Dietrich

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 48, Page(s) e2315503120

Abstract: Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory ... ...

Abstract	Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acute
MeSH term(s)	Animals ; Mice ; Gasdermins ; Salmonella Infections/prevention & control ; Salmonella typhimurium ; Inflammation ; Epithelial Cells ; Inflammasomes
Chemical Substances	Gasdermins ; Inflammasomes
Language	English
Publishing date	2023-11-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2315503120
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Article: Epithelial inflammasomes in the defense against Salmonella gut infection

Fattinger, Stefan A / Sellin, Mikael E / Hardt, Wolf-Dietrich

Current opinion in microbiology. 2021 Feb., v. 59

2021

Abstract	The gut epithelium prevents bacterial access to the host's tissues and coordinates a number of mucosal defenses. Here, we review the function of epithelial inflammasomes in the infected host and focus on their role in defense against Salmonella Typhimurium. This pathogen employs flagella to swim towards the epithelium and a type III secretion system (TTSS) to dock and invade intestinal epithelial cells. Flagella and TTSS components are recognized by the canonical NAIP/NLRC4 inflammasome, while LPS activates the non-canonical Caspase-4/11 inflammasome. The relative contributions of these inflammasomes, the activated cell death pathways and the elicited mucosal defenses are subject to environmental control and appear to change along the infection trajectory. It will be an important future task to explain how this may enable defense against the challenges imposed by diverse bacterial enteropathogens.
Keywords	Salmonella Typhimurium ; cell death ; enteropathogens ; flagellum ; inflammasomes ; microbiology
Language	English
Dates of publication	2021-02
Size	p. 86-94.
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2020.09.014
Database	NAL-Catalogue (AGRICOLA)

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Article: Does change of responsibility reduce escalating commitment? A replication and theoretical extension

Schultze, Thomas / Schulz-Hardt, Stefan

Journal of Experimental Psychology - Applied

2022 Volume 28, Issue 1, Page(s) 189–204

Abstract: ... escalating commitment (i.e., the failure to withdraw from losing courses of action). This intervention is ...

Title translation	Verringert der Wechsel der Verantwortung das eskalierende Engagement? Eine Replikation und theoretische Erweiterung
Abstract	Reassigning responsibility is the most prominent and best-replicated intervention against escalating commitment (i.e., the failure to withdraw from losing courses of action). This intervention is considered effective because it reduces reinvestments after negative feedback in decision scenarios with a single reinvestment decision. However, we argue that any intervention against escalating commitment should fulfill two additional criteria. The first is temporal stability, that is, the beneficial effects of the intervention need to persist beyond a single reinvestment decision. The second is specific effectiveness, that is, the intervention should reduce commitment only if the project continues to fail after an initial setback (structural failure) but not if it recovers and is ultimately profitable (temporary failure). To subject reassignment of responsibility to this critical test of effectiveness, we introduce a modification of the escalation paradigm that allows testing for temporal stability and differentiates between structural and temporary failure. In the first of two experiments, we did not find evidence of temporal stability. Experiment 2 found persistent short-term effects of responsibility reassignment, but these effects were unspecific, reducing commitment to both losing and ultimately successful courses of action. Our findings question the usefulness of responsibility reassignment as an effective intervention against escalating commitment. Public Significance Statement: This study subjects the most prominent intervention against the escalation of commitment, reassigning responsibility for reinvestment decisions, to a critical test. Our results caution against using this intervention, as its effects are short-lived, and changing responsibility entails the risk of reducing the commitment to ultimately successful projects.
Keywords	Choice Behavior ; Cognitive Processes ; Commitment ; Decision Making ; Entscheidungsfindung ; Failure ; Feedback ; Intervention ; Kognitive Prozesse ; Misserfolg ; Responsibility ; Verantwortlichkeit ; Verpflichtung ; Wahlverhalten
Language	English
Document type	Article
ZDB-ID	2103149-6
ISSN	1939-2192 ; 1076-898X
ISSN (online)	1939-2192
ISSN	1076-898X
DOI	10.1037/xap0000366
Database	PSYNDEX

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