ArgR-dependent Bacterial Resistance to Host Lipid Droplets in Edwardsiella piscicida
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase
PROVIDER: MTBLS9590 | MetaboLights | 2025-07-04
REPOSITORIES: MetaboLights
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| LD101_processed.zip | Other | |||
| LD201_processed.zip | Other | |||
| PBS101_processed.zip | Other | |||
| PBS201_processed.zip | Other | |||
| QC101_processed.zip | Other |
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Project description:The inducible innate immune response to infection requires a concerted process of gene expression that is regulated at multiple levels. Most global analyses of the innate immune response have focused on transcription induced by defined immunostimulatory ligands, such as lipopolysaccharide. However, the response to pathogens involves additional complexity, as pathogens interfere with virtually every step of gene expression. How cells respond to pathogen-mediated disruption of gene expression to nevertheless initiate protective responses remains unclear. We previously discovered that a pathogen-mediated blockade of host protein synthesis provokes the production of specific pro-inflammatory cytokines. It remains unclear how these cytokines are produced despite the global pathogen-induced block of translation. We addressed this question by using parallel RNAseq and ribosome profiling to characterize the response of macrophages to infection with the intracellular bacterial pathogen Legionella pneumophila. Our results reveal that mRNA superinduction is required for the inducible immune response to a bacterial pathogen.
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Project description:<p>Lipids, fundamental constituents of cell membranes, cellular energy carriers, and signaling molecules, play a pivotal role in the interaction between pathogens and hosts. During microbial infections, lipids not only fuel the activation of the immune system but also, acting as signaling molecules, participate in crucial biological processes such as inflammation initiation, macrophage polarization, and adaptive immune regulation. Serving as the primary reservoirs of neutral lipids within host cells, lipid droplets (LDs) function as the regulatory hub for cellular lipid metabolism and immune responses. Following lipopolysaccharide (LPS) stimulation, mouse (Mus musculus) deploy a diverse array of proteins, including those with antiviral and antibacterial activities, along with regulatory proteins of the immune system, onto immune cell lipid droplets. This action suppresses the interaction between LDs and mitochondria, thereby coordinates host metabolic and immune reactions to combating infections. How LDs in fish are reprogramed by bacterial infections in aspects of their metabolisms and anti-infection reaction remains insufficiently elucidated.</p><p>Employing turbot (Scophthalmus maximus) as the model organism, this study employs comparative proteomics to systematically screen alterations in the protein composition of liver LDs pre- and post- infection. This endeavor preliminarily illuminates the metabolic and immune-regulatory functions that LDs exhibit in response to pathogenic bacterial incursions. It was observed that the LDs of turbot contain a substantial amount of histones with antibacterial properties. Post bacterial infection, the liver of turbot orchestrates the recruitment of a plethora of proteins, essential for purine nucleotide metabolism, fatty acid oxidation, oxidative phosphorylation and ADP/ATP turnover, onto LDs. This orchestrated effort culminates in the reprogramming of metabolic pathways to counteract bacterial invasions, signifying the extensive involvement of fish LDs in the regulatory nexus of anti-infective immune responses. Furthermore, it was observed that the absence of the T3SS in the Edwardsiella piscicida mutants leads to marked alterations in the levels of ferroptosis related proteins, such as ACSL4 and FSP1, on LDs. This implies that LDs may mediate bactericidal activities either through the direct recruitment of antimicrobial proteins or peptides or by modulating cellular ferroptosis to activate anti-infective immune responses. Correspondingly, unsaturated fatty acids (UFAs) within the host can attenuate bacterial virulence by directly binding to the central regulatory protein EsrC, thereby suppressing the expression of the T3SS and impairing bacterial virulence.</p><p>To counteract LD and lipid-mediated antibacterial immunity, pathogenic microorganisms have evolved various mechanisms to interfere with host LD metabolism. The genes related to LD tolerance were systematically screened in fish pathogen E. piscicida with Tn-seq technology, and four genes such as ETAE_2018, flgH, evpG, and uxaB were identified as those related to bacterial LD tolerance. The notable effect of EvpG, a component of the T6SS, implied that E. piscicida might actively modulate host LD metabolism through a virulence secretion system. Systematic screening reveals that E. piscicida could actively inhibit the accumulation of LDs in host cells during infection through the T3SS effectors, EseO (ETAE_1604) and EseP (ETAE_3282). 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EseO, EseP, and their derivatives may provide new candidate drug molecules for the treatment of lipid metabolism-related diseases in humans and animals, and also offer insights into the development of novel aquaculture vaccines and disease control strategies.</p>
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Project description:Background: It has been shown that intracellular pathogens hijack DC functions to evade immune defense mechanisms. In this study, we investigated the responses of human monocyte derived DCs to four intracellular bacteria, Tropheryma whipplei, Coxiella burnetii, Brucella abortus and Orientia tsutsugamushi, responsible for human infectious diseases and known to infect myeloid cells. Methods: Whole genome microarrays were assessed to define common and specific transcriptionnal responses to bacterial pathogen. Bacterial pathogen ability to affect DC maturation was assessed by measuring lymphoproliferation and endocytosis as well as phenotypic maturation markers (CD80, CD83, CD86 and HLA-DR) expression. Results: We found that Coxiella burnetii, Orientia tsutsugamushi and Brucella abortus induced DC maturation assessed through decreased endocytosis ability, triggering lymphoproliferation, surface expression of HLA class II molecules and phenotypic changes, whereas Tropheryma whipplei did not induce DC maturation. As revealed by microarray analysis, the response of DCs to these bacteria consisted of a core associated with the maturation of DCs and signatures specific for each pathogen. The core response represented 10% of genes modulated in response to pathogens and consisted of general cellular processes including nucleotide binding, protein transport, cell fraction, protein kinase, cell cycle, mitochondrial membrane and cytoskeleton. The specific transcriptional signature induced by C. burnetii is associated with the communication between innate and adaptive immune cells and DC maturation. B. abortus signature specifically involved arachidonic acid and lipooxygenase pathways and O. tsutsugamushi signature involved type I and type III IFN responses. Conclusion: This study demonstrates that intracellular bacteria use multifaceted pathways to induce DC maturation which may lead to unadapted immune response. The understanding of these pathways may be useful to improve our knowledge of bacterial recognition by the immune system but also intracellular bacterial diseases.
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