Alleviation of monocyte exhaustion by BCG derivative mycolic acid
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ABSTRACT:
PROVIDER: PRJNA1014905 | ENA |
REPOSITORIES: ENA
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Project description:Monocyte exhaustion characterized by sustained pathogenic inflammatory and immune-suppressive features underlies the pathogenesis of sepsis induced by systemic polymicrobial infections. However, effective strategies in blocking monocyte exhaustion and restoring innate homeostasis are currently not available. In this study, we found that Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium Bovis Bacillus Calmette–Guérin (BCG), to be a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA can effectively block the expansion of exhausted Ly6Chi /CD38hi/PD-L1hi monocytes induced by repetitive LPS challenges, and restore the expression of immune-enhancing CD86 on co-treated monocytes. Functionally, M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Mechanistically, M-MA exerts its protective effects independent of cellular receptor TREM2, and relieves cellular stress signaling through blocking Src-STAT1 mediated pathogenic inflammatory polarization as well as reducing the production of compensatory immune suppressors TAX1BP1 and PLAC8. Our whole genome methylation analyses further revealed that M-MA can effectively erase methylation memory of exhausted monocytes, with validated restoration of plac8 methylation by M-MA. Together, our data reveal M-MA as a potent agent in restoring monocyte homeostasis with future therapeutic potential for the treatment of sepsis.
2023-12-19 | GSE242825 | GEO
Project description:Monocyte exhaustion with sustained pathogenic inflammation and immune-suppression, a hallmark of sepsis resulting from systemic infections, presents a challenge with limited therapeutic solutions. This study identified Methoxy-Mycolic Acid (M-MA), a branched mycolic acid derived from Mycobacterium bovis Bacillus Calmette-Guérin (BCG), as a potent agent in alleviating monocyte exhaustion and restoring immune homeostasis. Co-treatment of monocytes with M-MA effectively blocked the expansion of Ly6Chi/CD38hi/PD-L1hi monocytes induced by LPS challenges and restored the expression of immune-enhancing CD86. M-MA treatment restored mitochondrial functions of exhausted monocytes and alleviated their suppressive activities on co-cultured T cells. Independent of TREM2, M-MA blocks Src-STAT1-mediated inflammatory polarization and reduces the production of immune suppressors TAX1BP1 and PLAC8. Whole genome methylation analyses revealed M-MA's ability to erase the methylation memory of exhausted monocytes, particularly restoring Plac8 methylation. Together, our data suggest M-MA as an effective agent in restoring monocyte homeostasis with a therapeutic potential for treating sepsis.
| S-EPMC10845070 | biostudies-literature
Project description:This experiment explored the transcriptional response of human peripheral blood mononuclear cells (PBMC) isolated from BCG-vaccinated individuals following 6 days of in vitro stimulation with 2x10^5 cfu of different Bacillus Calmette-Guérin (BCG) strains or 100 ng/ml Mycobacterium tuberculosis-derived purified protein derivative (PPD). The BCG strains used were BCG Russia (Russian BCG-I sub-strain), BCG Japan (Tokyo 172 sub-strain), BCG Denmark (Danish 1331 sub-strain) & BCG Pasteur.
2022-01-26 | E-MTAB-11345 | biostudies-arrayexpress
Project description:Cattle were vaccinated at week 0 with the live attenuated M. bovis BCG SSI vaccine strain; some animals remain as non-vaccinated controls. After eight weeks animals were challenged intranodally with 108 BCG Tokyo cfu. Lymph nodes were harvested at week 11 and bacterial load in lymph nodes evaluated. Some BCG vaccinates had bacterial loads similar to those found in non-vaccinated animals (not-protected) and some animals had lower bacterial loads (protected) than non-vaccinated animals. Immune responses to mycobacteria were monitored in vitro by stimulation of whole blood with medium, purified protein derivative from M. bovis (PPD-B) or live BCG Tokyo longitudinally. Blood samples from 6 BCG-protected, 6 BCG-not-protected and 6 not-vaccinated. Challenged cattle stimulated with mycobacterial antigens or not were used to prepare RNA for RNAseq analysis at weeks 0 (vaccination), 8 (challenge), 9, 10 and 11. The outcome of this project would help not only in the selection of vaccine candidates but would also inform on the formulation of novel vaccines/vaccination strategies.
2018-07-30 | GSE84867 | GEO
Project description:Mycobacterium tuberculosis has a complex cell envelope that is remodelled throughout infection to respond and survive the hostile and variable intracellular conditions within the host. Despite the importance of cell wall homeostasis in pathogenicity, little is known about the environmental signals and regulatory networks controlling cell wall biogenesis in mycobacteria. The mycolic acid desaturase regulator (MadR) is a transcriptional repressor responsible for regulation of the essential aerobic desaturases desA1 and desA2 that are differentially regulated throughout infection along with mycolate modification genes and thus, likely involved in mycolic acid remodelling. Here we generated a madR null mutant in M. smegmatis that exhibited traits of an impaired cell wall with increased permeability, susceptibility to rifampicin and cell surface disruption as a consequence of desA1/desA2 dysregulation. Analysis of mycolic acids revealed the presence of a highly desaturated mycolate in the null mutant that exists in relative trace amounts in the wildtype, but increases in abundance upon cell surface disruption as a result of relieved repression on the desA1/desA2 promoters. Transcriptomic profiling confirmed MadR as a cell surface disruption responsive regulator of desA1/desA2 and further implicating it in the control of bespoke β-oxidation pathways and transport evolutionarily diversified subnetworks associated with virulence. In vitro characterisation of MadR using electromobility shift assays and analysis of binding affinities is suggestive of a unique acyl-CoA pool sensing mechanism, whereby MadR is able to bind a range of acyl-CoA but MadR repression of desA1/desA2 promoters is only relieved upon binding of saturated acyl-CoA of chain length C16-C24. We propose this acyl effector ligand mechanism as distinct to other regulators of mycolic acid biosynthesis or fatty acid desaturases and places MadR as the key regulatory checkpoint that coordinates mycolic acid remodelling in response to host derived cell surface perturbation
2022-01-01 | GSE171759 | GEO
Project description:We constructed mycolic acid synthesis key gene pks13 mutant strain and analyzed its impacts on whole cell at gene expression level compared to the wild-type ATCC13869.
2018-01-01 | GSE104833 | GEO
Project description:The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated the BCG-specific gene expression changes induced in PBMCs and CD4 memory T cells by BCG in individuals pre- and 8m post vaccination. We also determined whether reactivity against a peptide pool defined in individuals with controlled latent TB infection (MTB300), and with peptides homologous to peptides found in BCG, was boosted following BCG vaccination.
2021-12-06 | GSE156422 | GEO
Project description:Transcriptomics on lung-resident CD8+ T cells reveals how global gene expression patterns diverge over the course of infection with virulent Mtb and non-pathogenic BCG strains. CD8+ T cells from Mtb-infected animals respond with a stronger activation profile than cells from BCG-infected animals, promoting a more inflammatory gene expression profile that contributes to increased indicators of T cell exhaustion, apoptosis and metabolic reprogramming. These data provide new insights into the differential regulation of T cell immunity in virulent and non-virulent Mycobacterial infections.
2019-12-10 | GSE117330 | GEO
Project description:Analysis of PBMC from 10 week old infants vaccinated with BCG at birth. During follow-up 26 infants developed tuberculosis (TB) (non-protected by BCG) and 20 infants did not develop TB despite documented exposure (protected by BCG). PBMC were stimulated with media only or reconstituted BCG for 4 and 12 hours. Results provide insight into the mechanisms behind the failure of BCG to protect against disease.
2014-06-30 | GSE20716 | GEO
Project description:Patients with high-risk non-muscle-invasive bladder carcinoma (NMIBC) frequently relapse after standard BCG immunotherapy and have a dismal outcome after progression to muscle-invasive bladder carcinoma (MIBC). Although BCG induces potent inflammatory responses upon intravesical instillations, the mechanisms of tumor resistance to such immunotherapy remain elusive. We performed a longitudinal immune profiling of a cohort of MIBC pre- and post BCG therapy with gene and protein expression analysis to establish correlations with 5 year clinical follow up. Here, we demonstrate two distinct patterns of BCG-induced immunosubversion, which include acquired immune resistance and tumor-cell intrinsic resistance. Firstly, intracellular BCG infection of a subset of urothelial carcinoma cells downregulated HLA-I expression and induced epithelial to mesenchymal transition (EMT) characteristics. BCG treated tumors exhibiting such HLA class I loss displayed an immune desert tumor microenvironment dominated by myeloid immunosuppressive cells. Such patients presented with early cancer relapses and a bad outcome. Conversely, BCG-treated tumors which did not lose HLA class I antigens at relapse displayed an immune escape mechanism dominated by a Th1 pattern with high expression of inhibitory checkpoints and exhaustion markers. Such patients had a favorable outcome upon second surgery. We surmise that HLA class I expression does not result from immunoediting but rather from an EMT process associated to myeloid immunosuppression that predicts dismal prognosis.
2022-05-05 | GSE199471 | GEO