Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1093608 | ENA |
REPOSITORIES: ENA
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Project description:Through releasing virulence molecules into host cells, intracellular bacteria interfere with host cellular functions and grow in the cells that engulf them. To ensure survival and virulence, these pathogens also manipulate host factors, but this process is not fully understood. In this study, we investigated the host molecular mechanisms required for intracellular bacterial growth in macrophages using Salmonella typhimurium (Salmonella) infection model and bacterial division reporter system. Upon Salmonella infection, Protein Phosphatase 6 (Pp6) was significantly reduced in macrophages containing growing bacteria. Conditional knockout of Pp6 increased host susceptibility to Salmonella-mediated killing, which was attributed to the poor resistance in Pp6-deficient macrophages. MicroRNA-31 (miR-31) was identified as a negative regulator of Pp6, and its conditional deletion promoted Salmonella clearance. Moreover, a yeast two-hybrid screening identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (Pfkfb1), a key metabolic regulator, as a substrate of Pp6. Pp6-deficient macrophages exhibited elevated Pfkfb1 expression. Furthermore, we found that macrophages containing growing Salmonella exclusively exhibited high Pfkfb1 expression. Pfkfb1 deletion reduced bacterial growth, likely due to increased NO levels, while also downregulating arginase-1 (Arg-1) expression and impairing arginine biosynthesis and metabolism in macrophages. Together, we investigated the role of Pp6-Pfkfb1 axis in orchestrating host metabolic adaptions and intracellular bacterial survival, which may provide therapeutic targets for infectious diseases against intracellular multidrug-resistant bacteria.
2025-11-20 | GSE291689 | GEO
Project description:The upsurge of multidrug-resistant infections has rendered tuberculosis the principal cause of death among infectious diseases. A clonal outbreak multidrug-resistant triggering strain of Mycobacterium tuberculosis was identified in Kanchanaburi Province, designated “MKR superspreader”, which was found to subsequently spread to other regions, as revealed by prior epidemiological reports in Thailand. Herein, we showed that the MKR displayed a higher growth rate upon infection into host macrophages in comparison with the H37Rv reference strain. To further elucidate the MKR’s biology, we utilised RNA-Seq and differential gene expression analyses to identify host factors involved in the intracellular viability of the MKR. A set of host genes function in the cellular response to lipid pathway was found to be uniquely up-regulated in host macrophages infected with the MKR, but not those infected with H37Rv. Within this set of genes, the IL-36 cytokines which regulate host cell cholesterol metabolism and resistance against mycobacteria attracted our interest, as our previous study revealed that the MKR elevated genes associated with cholesterol breakdown during its growth inside host macrophages. Indeed, when comparing macrophages infected with the MKR to H37Rv-infected cells, our RNA-Seq data showed that the expression ratio of IL-36RN, the negative regulator of the IL-36 pathway, to that of IL-36G was greater in macrophages infected with the MKR. Furthermore, the intracellular survival of MKR was diminished with decreased IL-36RN expression. Overall, our results indicate that IL-36RN is critical for MKR intracellular survival and could serve as a new target against this emerging multidrug-resistant M. tuberculosis strain.
2022-10-28 | GSE194017 | GEO
Project description:Bacterial infectious diseases have posed a serious challenge to public health, often resulting in treatment failure and infection recurrence due to the emergence of drug-resistant bacteria. Owing to inaccessible binding sites, pathogens can evade attack from host immune cells and traditional antibiotics, leading to local immunosuppressive status. Our study reports a novel bacteriophage-based immune scavenger labeling nanoplatform (Mn2+@Man-phage) to combat immune-evasive bacteria and reverse immunosuppressive status. Our nanosystem utilizes the inherent bacterium-targeting ability of bacteriophages to aggregate at infection sites and mediates mannose-dependent recognition, phagocytosis, and killing of bacteria by macrophages, while the released Mn2+ amplifies the antibacterial immune efficacy. Consequently, macrophages polarize towards M1 and secrete various pro-inflammatory factors, effectively clearing bacteria. Moreover, reprogramming macrophages directly activate T cells at infection sites, eliciting potent adaptive antibacterial immune responses and ultimately achieving bacterial eradication. Overall, we demonstrate a universal strategy for pathogen targeting and immunomodulation of macrophages against bacterial infection.
2025-01-11 | GSE271238 | GEO
Project description:Bacterial infectious diseases have posed a serious challenge to public health, often resulting in treatment failure and infection recurrence due to the emergence of drug-resistant bacteria. Owing to inaccessible binding sites, pathogens can evade attack from host immune cells and traditional antibiotics, leading to local immunosuppressive status. Our study reports a novel bacteriophage-based immune scavenger labeling nanoplatform (Mn2+@Man-phage) to combat immune-evasive bacteria and reverse immunosuppressive status. Our nanosystem utilizes the inherent bacterium-targeting ability of bacteriophages to aggregate at infection sites and mediates mannose-dependent recognition, phagocytosis, and killing of bacteria by macrophages, while the released Mn2+ amplifies the antibacterial immune efficacy. Consequently, macrophages polarize towards M1 and secrete various pro-inflammatory factors, effectively clearing bacteria. Moreover, reprogramming macrophages directly activate T cells at infection sites, eliciting potent adaptive antibacterial immune responses and ultimately achieving bacterial eradication. Overall, we demonstrate a universal strategy for pathogen targeting and immunomodulation of macrophages against bacterial infection.
2025-01-13 | GSE272212 | GEO
Project description:Phage therapy is a promising adjunct therapeutic approach against bacterial multidrug-resistant infections, including Pseudomonas aeruginosa-derived infections. Nevertheless, the current knowledge about the phage-bacteria interaction within a human environment is limited. In this work, we performed a transcriptome analysis of phage-infected P. aeruginosa adhered to a human epithelium (Nuli-1 ATCC® CRL-4011™). To this end, we performed RNA-sequencing from a complex mixture comprising phage–bacteria–human cells at early, middle, and late infection and compared it to uninfected adhered bacteria. Overall, we demonstrated that phage genome transcription is unaltered by bacterial growth and phage employs a core strategy of predation through upregulation of prophage-associated genes, a shutdown of bacterial surface receptors, and motility inhibition. In addition, specific responses were captured under lung-simulating conditions, with the expression of genes related to spermidine syntheses, sulfate acquisition, spermidine syntheses, biofilm formation (both alginate and polysaccharide syntheses), lipopolysaccharide (LPS) modification, pyochelin expression, and downregulation of virulence regulators. These responses should be carefully studied in detail to better discern phage-induced changes from bacterial responses against phage. Our results establish the relevance of using complex settings that mimics in vivo conditions to study phage-bacteria interplay, being obvious the phage versatility on bacterial cell invasion.
2023-05-31 | GSE213159 | GEO
Project description:Antibiotic therapy is highly effective for treating infectious diseases, but the key factors determining its clinical efficacy are not fully understood. Here, we show that itaconate (ITA), a metabolite produced by macrophages, has dual anti-infective effects against multidrug-resistant Klebsiella pneumoniae both in vitro and in vivo. In bacteria, ITA activates the TCA cycle and respiratory complex I, increasing intracellular pH. This downregulates molecular chaperones DksA and DnaK, suppresses the RpoS-mediated stress response, and restores colistin susceptibility against mcr-positive bacteria. In the host, ITA induces glycolytic reprogramming and lactate accumulation in infected macrophages, driving protein lactylation and promoting the pro-inflammatory M1 phenotype. Lysine lactylation of serine hydroxymethyltransferase 2 (SHMT2), a mitochondrial enzyme involved in one-carbon metabolism, is a key event linking ITA metabolism to immune activation. Lactylated SHMT2 inhibits prolyl hydroxylase (PHD) activity, stabilizes HIF-1α, and activates downstream transcriptional programs, including TNF and PTGS2, thereby enhancing M1 polarization. Genetic deletion or K464R mutation of SHMT2 abolishes these effects and negates ITA-induced bacterial clearance. Our findings reveal a ITA-driven metabolic reprogramming strategy that simultaneously reprograms bacterial metabolism to reverse colistin resistance and activates the SHMT2–HIF-1α axis via lactylation to boost macrophage antimicrobial responses.
2025-11-04 | PXD070266 |
Project description:Antibiotic therapy is highly effective for treating infectious diseases, but the key factors determining its clinical efficacy are not fully understood. Here, we show that itaconate (ITA), a metabolite produced by macrophages, has dual anti-infective effects against multidrug-resistant Klebsiella pneumoniae both in vitro and in vivo. In bacteria, ITA activates the TCA cycle and respiratory complex I, increasing intracellular pH. This downregulates molecular chaperones DksA and DnaK, suppresses the RpoS-mediated stress response, and restores colistin susceptibility against mcr-positive bacteria. In the host, ITA induces glycolytic reprogramming and lactate accumulation in infected macrophages, driving protein lactylation and promoting the pro-inflammatory M1 phenotype. Lysine lactylation of serine hydroxymethyltransferase 2 (SHMT2), a mitochondrial enzyme involved in one-carbon metabolism, is a key event linking ITA metabolism to immune activation. Lactylated SHMT2 inhibits prolyl hydroxylase (PHD) activity, stabilizes HIF-1α, and activates downstream transcriptional programs, including TNF and PTGS2, thereby enhancing M1 polarization. Genetic deletion or K464R mutation of SHMT2 abolishes these effects and negates ITA-induced bacterial clearance. Our findings reveal a ITA-driven metabolic reprogramming strategy that simultaneously reprograms bacterial metabolism to reverse colistin resistance and activates the SHMT2–HIF-1α axis via lactylation to boost macrophage antimicrobial responses.
2025-11-04 | PXD070276 |
Project description:Acinetobacter baumannii is currently a major threat to human health. With the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the development of complementary strategies is needed. A promising complimentary and realistic strategy could be phage therapy, which uses bacteriophages (phages), i.e viruses that specifically infect and kill bacterial cells during their life cycle. We designed a two-phage cocktail highly efficient against an extensive drug-resistant (XDR) A. baumannii isolate collected from a patient with burn wound infection at CHUV (termed Ab125). A first in vitro screen of our collection of 34 different phages identified only phage vB_AbaM_3098 as capable of lysing Ab125. However, quick selection of phage-resistant clones (termed Ab139) occurred. Comparative genomics and proteomics between Ab125 and Ab139 revealed several key variations. Very interestingly, we observed that Ab139 became susceptible to six different phages in the collection, otherwise inactive on Ab125. Phage-resistance was also selected when Ab139 was challenged with either of the six phages, with bacterial regrowth observed between 14 h and 16 h. However, combination of vB_AbaM_3098 and vB_AbaM_3014 led to a two-phage cocktail capable of totally inhibiting the growth of Ab125. Treatment with the phage cocktail led to 90% survival after 5 days in the in vivo Galleria Mellonella model of infectious diseases, compared to 0% in the non-treated group. We show that the combination of a phage that only slightly shifted the in vitro bacterial growth curve with an “inactive phage” led to the formulation of a highly bactericidal phage cocktail against Ab125. We then tested the therapeutic potential of the assembled cocktail in synergy with antibiotics and found a synergy with colistin. This work highlights the complexity sometimes involved in the assembly of potent phage cocktail.
2025-12-08 | PXD062593 | Pride
Project description:Objectives: Colistin remains a last-line treatment for multidrug-resistant Acinetobacter baumannii and combined use of colistin and carbapenems has shown synergistic effects against multidrug-resistant strains. In order to understand the bacterial responses to these antibiotics we analysed the transcriptome of A. baumannii following exposure to each.
2014-11-30 | GSE62794 | GEO