Host inflammasome defense mechanisms and bacterial pathogen evasion strategies

Brewer, Susan; Brubaker, Sky W.; Monack, Denise M.

doi:10.1016/j.coi.2019.05.001

Cited by 39 publications

(32 citation statements)

References 63 publications

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“…For an adapted pathogen like S. Tm, this task is complicated by the bacterium's evolved ability to evade PRR recognition, through e.g., context-dependent regulation of its gene expression or inhibition of host-cell signaling. 1,24,25 Inflammasomes are multimeric signaling complexes that assemble in the host cell cytosol upon sensing of PAMPs or cellular damage by PRRs of the Nod-like receptor family (NLRs; NLRP1, NLRP3, NLRC4), Aim2, or Pyrin. 26 Inflammasome assembly causes cleavage of pro-inflammatory Caspase-1, 27 secretion of RESULTS NAIP/NLRC4 potently restricts S. Tm migration from the gut lumen to systemic sites Our in vivo analysis of the NAIP/NLRC4-mediated defense focused on the S. Tm infection dynamics during the first 24h after orogastric inoculation in the Streptomycin pretreated mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…Such compartmentspecific down regulation has been observed previously in various infection models. 25,[80][81][82] S. Tm requires TTSS-1 and flagella (composed of flagellin subunits) for the initial colonization and establishment of gut infection. 16,72 Especially for invasion of IECs, which strongly express Naip1, 2, 5, 6, and Nlrc4 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

et al. 2020

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Inflammasomes can prevent systemic dissemination of enteropathogenic bacteria. As adapted pathogens including Salmonella Typhimurium (S. Tm) have evolved evasion strategies, it has remained unclear when and where inflammasomes restrict their dissemination. Bacterial population dynamics establish that the NAIP/NLRC4 inflammasome specifically restricts S. Tm migration from the gut to draining lymph nodes. This is solely attributable to NAIP/NLRC4 within intestinal epithelial cells (IECs), while S. Tm evades restriction by phagocyte NAIP/NLRC4. NLRP3 and Caspase-11 also fail to restrict S. Tm mucosa traversal, migration to lymph nodes, and systemic pathogen growth. The ability of IECs (not phagocytes) to mount a NAIP/NLRC4 defense in vivo is explained by particularly high NAIP/NLRC4 expression in IECs and the necessity for epithelium-invading S. Tm to express the NAIP1-6 ligandsflagella and type-III-secretion-system-1. Imaging reveals both ligands to be promptly downregulated following IEC-traversal. These results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.Mucosal Immunology (2020) 13:530-544; https://doi.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

et al. 2020

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“…This cytokine release is often accompanied by a rapid cell death (pyroptosis). Inflammasome sensors oligomerize to recruit and activate the caspase‐1 or caspase‐11 cell death proteases, which in turn cleave pro‐IL‐1β and pro‐IL‐18 to their biologically active forms (for reviews see [1, 2]). PAMP activation for release of cytokines by inflammasomes is a two‐step process.…”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

Greaney

Portley

O’Mard

et al. 2020

Journal of Leukocyte Biology

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Anthrax lethal toxin (LT) is a protease that activates the NLRP1b inflammasome sensor in certain rodent strains. Unlike better‐studied sensors, relatively little is known about the priming requirements for NLRP1b. In this study, we investigate the rapid and striking priming‐independent LT‐induced release of IL‐1β in mice within hours of toxin challenge. We find IL‐1β release to be a NLRP1b‐ and caspase‐1‐dependent, NLRP3 and caspase‐11‐independent event that requires both neutrophils and peptidyl arginine deiminiase‐4 (PAD4) activity. The simultaneous LT‐induced IL‐18 response is neutrophil‐independent. Bone marrow reconstitution experiments in mice show toxin‐induced IL‐1β originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL‐1β, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL‐1β, they were unable to bind or endocytose LT and did not secrete IL‐1β in response to the toxin. LT‐treated mice had higher levels of cell‐free DNA and HMGB1 in circulation than PBS‐treated controls, and treatment of mice with recombinant DNase reduced the neutrophil‐ and NLRP1‐dependent IL‐1β release. DNA sensor AIM2 deficiency, however, did not impact IL‐1β release. These data, in combination with the findings on PAD4, suggest a possible role for in vivo NETs or cell‐free DNA in cytokine induction in response to LT challenge. Our findings suggest a complex interaction of events and/or mediators in LT‐treated mice with the neutrophil as a central player in induction of a profound and rapid inflammatory response to toxin.

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“…Salmonella has evolved many strategies to counter or evade immune responses during establishment of infection. However, while the modulation of innate immune responses during infection with this pathogen is well studied (21)(22)(23)(24), the strategies which Salmonella employs to evade T-cell-mediated immune responses have not been investigated in detail (25)(26)(27). Salmonella has been shown to inhibit CD4 T cell activation in vitro by bringing about downregulation of the T cell receptor and by inducing negative modulators of T cell activation (28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2

et al. 2020

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Pathogenic Salmonella serovars are a major cause of enteric illness in humans and animals, and produce clinical manifestations ranging from localized gastroenteritis to systemic disease. T cells are a critical component of immunity against this intracellular pathogen. The mechanisms by which Salmonella modulates T-cell-mediated immune responses in order to establish systemic infection are not completely understood. We show that infection of mice with Salmonella enterica serovar Typhimurium (S. Typhimurium) suppresses IL-2 and increases IFN-γ and IL-17 production from T cells activated in vivo or ex vivo through the T cell receptor. Infection with S. Typhimurium brings about recruitment of CD11b + Gr1 + suppressor cells to the spleen. Ex vivo depletion of these cells restores the ability of activated T cells to produce IL-2 and brings secretion of IFN-γ and IL-17 from these cells back to basal levels. The reduction in IL-2 secretion is not seen in IFN-γ −/− and iNOS −/− mice infected with Salmonella. Our findings demonstrate that sustained innate activated IFN-γ production during progression of infection with Salmonella reduces IL-2-secreting capability of T cells through an iNOS-mediated signaling pathway that can adversely affect long term immunity against this pathogen.

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Host inflammasome defense mechanisms and bacterial pathogen evasion strategies

Cited by 39 publications

References 63 publications

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2

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