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K. pneumoniae induced metabolic stress promotes immunotolerance

ABSTRACT: Metabolites generated in response to infection have a major role in shaping the nature of the immune response. We predicted that the metabolic response to the highly prevalent Klebsiella pneumoniae sequence type 258 (Kp ST258) strains is responsible for their ability to persist in the lungs, despite the expected proinflammatory signaling evoked by LPS. By combining in situ metabolic imaging and comprehensive transcriptional analyses, we demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation (FAO), generating an oxidant-rich microenvironment predisposed to the accumulation of anti-inflammatory monocyte populations. In a setting not unlike that generated by some tumors, metabolically active Kp ST258 elicits an immunotolerant, instead of a proinflammatory response. The bacteria in turn adapt to airway oxidants by upregulation of the Type VI Secretion System (T6SS), which is highly conserved across these strains worldwide. The global success of Kp ST258 can be explained, to a major extent, by their metabolic activity that promotes a permissive immune response to which the bacteria adapt.

ORGANISM(S): Klebsiella pneumoniae subsp. pneumoniae Mus musculus

PROVIDER: GSE184563 | GEO | 2022/08/09

REPOSITORIES: GEO

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K. pneumoniae induced metabolic stress promotes immunotolerance [single-cel RNA-seq]

Project description:Metabolites generated in response to infection have a major role in shaping the nature of the immune response. We predicted that the metabolic response to the highly prevalent Klebsiella pneumoniae sequence type 258 (Kp ST258) strains is responsible for their ability to persist in the lungs, despite the expected proinflammatory signaling evoked by LPS. By combining in situ metabolic imaging and comprehensive transcriptional analyses, we demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation (FAO), generating an oxidant-rich microenvironment predisposed to the accumulation of anti-inflammatory monocyte populations. In a setting not unlike that generated by some tumors, metabolically active Kp ST258 elicits an immunotolerant, instead of a proinflammatory response. The bacteria in turn adapt to airway oxidants by upregulation of the Type VI Secretion System (T6SS), which is highly conserved across these strains worldwide. The global success of Kp ST258 can be explained, to a major extent, by their metabolic activity that promotes a permissive immune response to which the bacteria adapt.

2022-08-09 | GSE190262 | GEO

Klebsiella pneumoniae-induced metabolic stress promotes immunotolerance

Project description:The metabolic stress associated with K. pneumoniae ST258 infection promotes immunosuppression and drives bacterial adaptation.

| PRJEB47143 | ENA

A Pathobiont of the Microbiota Balances Host Colonization and Intestinal Inflammation

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2010-06-01 | GSE20434 | GEO

Vaccine protection against multidrug-resistant Klebsiella pneumoniae in a non-human primate model of severe lower respiratory tract infection

Project description:Klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. The relative high burden of asymptomatic colonization by K. pneumoniae is often compounded by multidrug resistance-a potential problem for individuals with significant comorbidities or other risk factors for infection. A carbapenem-resistant K. pneumoniae strain classified as multilocus sequence type 258 (ST258) is widespread in the United States and can be resistant to many classes of clinically useful antibiotics. Thus, treatment of ST258 infections is often difficult. Inasmuch as new preventive and/or therapeutic measures are needed for treatment of such infections, we developed an ST258 pneumonia model in cynomolgus macaques and tested the ability of an ST258 capsule polysaccharide type 2 (CPS2) vaccine to moderate disease severity. Compared with sham-vaccinated animals, those vaccinated with ST258 CPS2 had significantly less disease as assessed by radiograph 24 h after intrabronchial installation of 108 CFUs of ST258. All macaques vaccinated with CPS2 ultimately developed ST258-specific antibodies that significantly enhanced serum bactericidal activity and killing of ST258 by macaque neutrophils ex vivo. Consistent with a protective immune response to CPS2, transcripts encoding inflammatory mediators were increased in infected lung tissues obtained from CPS-vaccinated animals compared with control, sham-vaccinated macaques. Taken together, our data provide support to the idea that vaccination with ST258 CPS can be used to prevent or moderate infections caused by ST258. As with studies performed decades earlier, we propose that this approach can be extended to include multiple capsule types

2019-11-26 | GSE137135 | GEO

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Project description:Bacteria have evolved effectors or toxins to outcompete other bacteria or to hijack host cell pathways. One broad family of bacterial polymorphic toxins regroups multidomain proteins with a modular organization, that comprise a C-terminal toxin domain fused to a N-terminal domain that adapt to the delivery apparatus. Polymorphic toxins include bacteriocins, contact-dependent growth inhibition systems, and specialized Hcp, VgrG, PAAR or Rhs Type VI secretion (T6SS) components. We recently described and characterized Tre23, a toxin domain fused to a T6SS-associated Rhs protein in Photorhabdus laumondii. Here, we show that the Rhs polymorphic toxin forms a complex with the T6SS spike protein VgrG and a cognate chaperone EagR. Using truncation derivatives and cross-linking mass spectrometry, we demonstrate that VgrG-EagR-Rhs complex formation requires the VgrG C-terminal β-helix and the Rhs Nterminal prePAAR and PAAR domains. We then report the cryo-electron-microscopy structure of the Rhs-EagR complex, demonstrating that the Rhs central region forms a β-barrel cage-like structure that encapsulates the C-terminal toxin domain, and provide evidence for processing of the Rhs protein through aspartyl autoproteolysis. We propose a model for Rhs loading on the T6SS, transport and delivery into the target cell.

2021-11-30 | PXD028652 | Pride

An Unexpected Role for Acetyl Coenzyme A Carboxylase in Metabolic Control of the Macrophage Acute Inflammatory Response

Project description:Macrophages must rapidly shift their cellular metabolism to facilitate the induction of the proinflammatory response, including activation of lipid synthesis pathways. However, the links between lipid metabolism and polarization in response to inflammatory signals remains unclear. Acetyl-CoA Carboxylase (ACC) is central to lipid synthesis, cellular energy utilization, and acetylation-dependent enzyme activation, but its role in macrophages remains unclear. To interrogate the role of ACC in the inflammatory response, we generated myeloid-specific LysMCre Acacafl/fl Acacbfl/fl ACC double knockout (ACCLysM) mice. Unexpectedly, myeloid-specific deletion or pharmacological inhibition of ACC attenuated lipopolysaccharide (LPS)-induced inflammation in mice, with decreased gene expression and protein levels of the proinflammatory cytokines IL-6 and IL-1. Using in vitro transcriptomics, lipidomics, and bioenergetics approaches we find that ACC deletion reestablishes the metabolic setpoint in macrophages and is required for metabolic rewiring in response to LPS- but not IL-4-dependent signaling. This translated to blunted phenotypic polarization to proinflammatory but not alternatively activating stimuli. Mechanistically, we identified that the metabolic rewiring that results from ACC deletion increased basal acetylation at histone H3 lysine 27 (H3K27Ac), a marker of active enhancers, which was reduced in response to LPS in ACC-deficient BMDMs. The failure of macrophages lacking ACC to adapt their glycolytic metabolism and polarize to inflammatory stimuli impaired macrophage proinflammatory effector functions. Taken together these data identify a novel role for ACC in metabolic and transcriptional regulation of the acute inflammatory response.

2023-01-04 | GSE193294 | GEO

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2022-02-23 | GSE185398 | GEO

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Project description:Bacteria of the genus Achromobacter are environmental germs, with an unknown reservoir, which can become opportunistic pathogens in immunocompromised patients, and be responsible for bacteremia, meningitis, pneumonia and peritonitis. Achromobacter xylosoxidans is an emerging pathogenic bacterium frequently isolated in the context of cystic fibrosis (CF). Recent studies show that A. xylosoxidans is involved in the degradation of the respiratory function of CF patients. The respiratory ecosystem of CF patients is colonized by bacterial species that constantly fight for space and access to nutrients. In particular, these bacteria use an antagonism system, a type VI secretion nanomachine (T6SS), which represents a virulence factor in many pathogenic bacteria. This study aimed to investigate the prevalence of the T6SS genes in Achromobacter xylosoxidans isolated in cystic fibrosis patient. We also evaluated clinical and molecular characteristics of T6SS-positive A. xylosoxidans strains. We have shown that A. xylosoxidans possesses a T6SS-encoded gene cluster and that some environmental and clinical isolates assemble a functional T6SS nanomachine. The A. xylosoxidans T6SS is used to target competitor bacteria, including other CF-specific pathogens. We gathered some evidences pointing toward a role of T6SS in CF-lung colonization: i, CF mimicking conditions trigger the activation of A. xylosoxidans T6SS; ii, we detected Hcp in the sputum of CF patient and iii, the T6SS helps internalization of A. xylosoxidans in lung epithelial cells. Our study highlights a new clinical determinant of the virulence of A. xylosoxidans as well as new diagnostic and therapeutic options in cystic fibrosis.

2024-02-01 | PXD031682 | Pride

The T6SSs of the entomopathogenic Photorhabdus laumondii revealed interbacterial competition and cross-link with diverse Photorhabdus-virulence mechanisms

Project description:Secretion systems are used as weapons by a variety of Gram-negative bacteria. Among them the Type VI Secretion System (T6SS) gained more interest throughout the last years. The system functions as a molecular nano-weapon: it is used in inter-kingdom competition by various bacteria to deliver toxic effectors in target cells. Here we describe the role of the T6SS in Photorhabdus laumondii subsp. laumondii strain DJC, an entomopathogenic biocontrol agent able to live in different environmental niches, such as in symbiosis with nematodes and in the rhizosphere on plant roots. Using bioinformatic and protein motif analyses we identified four T6SS gene clusters (T6SS-1, T6SS-2, T6SS-3 and T6SS-4) and multiple orphan T6SS related genes in the genome of P. laumondii. Furthermore, we highlighted 11 T6SS effector-immunity pairs, including three undescribed membrane disrupting effectors, each with putatively different antibacterial activities. By label-free mass spectrometry of P. laumondii wild type cells and respective T6SS-deficient strains, we could point out a cross-link between T6SS and other Photorhabdus’ virulence related mechanisms such as PVCs, T3SS and pyocins. Furthermore, a change in motility as well as in the secondary metabolism was observed upon T6SS-deficiency. Here, we shed light on the T6SS in P. laumondii DJC and suggesting a cross-link of various virulence mechanisms, which could help to gain knowledge on T6SS and better figure out the Photorhabdus ability to live in polymicrobial environments.

2024-04-05 | PXD035720 | Pride

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