Rv1906c mediated host immunomodulation
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ABSTRACT:
PROVIDER: PRJEB64201 | ENA |
REPOSITORIES: ENA
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Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection. Mice were infected with Mtb and treatment with PZA was started at 28 days post-infection. At 42 days and 63 days post-infection, group of animals were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. Mtb-infected, untreated animals served as controls.
2013-06-28 | E-GEOD-48027 | biostudies-arrayexpress
Project description:Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact on human and animal health worldwide. Mycobacterial life cycle is complex and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals when compared to uninfected controls are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls but protein levels increased as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggested that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recover to limit pathogen multiplication and promote survival that also facilitates pathogen transmission.
2016-03-10 | PXD003251 | Pride
Project description:Pyrazinamide (PZA) is one of the first line antibiotics used for the treatment of tuberculosis (TB). we have used human monocyte and a mouse model of pulmonary TB to investigate whether treatment with PZA, in addition to its known anti-mycobacterial properties, modulate the host immune response during Mycobacterium tuberculosis (Mtb) infection.
2013-06-28 | GSE48027 | GEO
Project description:Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis (TB) are incompletely understood. Here we show a role for eosinophils in host resistance to Mtb infection. In humans, eosinophils are found in resected human TB lung lesions and autopsy granulomas. Eosinophils are also found in granulomas in zebrafish, mice, and non-human primates, where they are functionally activated and degranulate. Transcriptional profiling of lung tissue after Mtb infection of mice, that selectively lack eosinophils, revealed changes in neuronal associated pathways. Importantly, employing several independent models of eosinophil deficiency in mice, we demonstrate that eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings establish an unexpected role for eosinophils, granulocytes typically associated with type II inflammation, in host resistance against Mtb, a major human bacterial pathogen.
2021-08-01 | GSE165871 | GEO
Project description:Suppression of chronic Arabidopsis immune responses is a widespread but typically strain-specific trait across the major bacterial lineages of the plant microbiota. Here, through phylogenetic analysis of 1,765 Xanthomonadales genomes, we show that immunomodulation is a highly conserved, ancestral trait across this core order of the plant microbiota, and preceded specialization of these bacteria as host-adapted pathogens. Rhodanobacter R179, from the deepest branch of the Xanthomonadales, activates immune responses which are dependent on EFR and SOBIR1 cell-surface receptor complexes, yet root transcriptomics suggest the commensal evades host recognition upon prolonged association. This commensal camouflage is likely due to the combined activities of the conserved ABC transporter permease (dssA) and the TonB-dependent transporter (dssB) and the selective elimination of immunogenic elicitors produced by R179, other microbiota members, and the plant host. The ability of R179 to mask itself and other commensals from host recognition is consistent with a convergence of distinct root transcriptomes triggered by immunosuppressive or non-suppressive synthetic communities upon R179 co-inoculation. Although root load of R179 on wild-type and efr fls2 sobir1 mutant plants was indistinguishable in mono-associations, immunomodulation through dssAB provided R179 with a competitive advantage in a community context in the absence of other immunosuppressive bacteria. Furthermore, root colonization of diverse commensal Xanthomonadales strains varied 1,000-fold without detrimental impacts on the host. We propose that conservation of immunomodulation by Xanthomonadales is related to their adaptation to terrestrial habitats and might have contributed to variation in strain-specific root association, which together accounts for their prominent role in plant microbiota establishment.
2024-12-12 | PXD045054 | Pride
Project description:LTBR-mediated immunomodulation of the tumor microenvironment promotes anti-tumor responses
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Project description:The global burden of tuberculosis (TB) is aggravated by the continuously increasing emergence of drug resistance, highlighting the need for innovative therapeutic options. The concept of host-directed therapy (HDT) as adjunctive to classical antibacterial therapy with antibiotics represents a novel and promising approach for treating TB. Here, we have focused on repurposing the clinically used anticancer drug tamoxifen, which was identified as a molecule with strong host-directed activity against intracellular Mycobacterium tuberculosis (Mtb). Using a primary human macrophage Mtb infection model, we demonstrate the potential of tamoxifen against drug-sensitive as well as drug-resistant Mtb bacteria. The therapeutic effect of tamoxifen was confirmed in an in vivo TB model based on Mycobacterium marinum infection of zebrafish larvae. Tamoxifen had no direct antimicrobial effects at the concentrations used, confirming that tamoxifen acted as an HDT drug. Furthermore, we demonstrate that the antimycobacterial effect of tamoxifen is independent of its well-known target the estrogen receptor (ER) pathway, but instead acts by modulating autophagy, in particular the lysosomal pathway. Through RNA sequencing and microscopic colocalization studies, we show that tamoxifen stimulates lysosomal activation and increases the localization of mycobacteria in lysosomes both in vitro and in vivo, while inhibition of lysosomal activity during tamoxifen treatment partly restores mycobacterial survival. Thus, our work highlights the HDT potential of tamoxifen and proposes it as a repurposed molecule for the treatment of TB.
2022-11-29 | GSE178919 | GEO
Project description:The outcome of an infectious disease exposure is the result of interactions between host and pathogen and can depend on genetic variations in both. We explored this relationship in tuberculosis (TB) by conducting a genome-to-genome (g2g) study of paired human and Mycobacterium tuberculosis (Mtb) genomes from a cohort of 1556 TB patients in Lima, Peru. We identified an association between a human intronic variant (rs3130660, OR = 10.06, 95% CI: 4.87 - 20.77, P = 7.92 ⨉ 10-8 ) in the FLOT1 gene and a subclade of Mtb Lineage 2 (g2g-L2). We assessed this interaction in a Mtb-macrophage infection model between bacterial and host genetic backgrounds. We found that expression of FLOT1 and other genes in the MHC class-I region are differentially modulated by g2g-L2 compared to nearest neighbor strains. We also found distinct inflammatory responses with different host genetic backgrounds, with hosts carrying the A allele of rs3130660 inducing stronger type I and II interferon (IFN) gene signatures than hosts carrying only the T allele. TB infection with g2g-L2 strains shift macrophage responses away from this IFN signaling. In vitro analyses show that the g2g-L2 strains are distinguished by altered redox states and resistance to reductive stress and that these phenotypes result from a single mutation in thioredoxin reductase (trxB2, T2N). We also investigated this association in a 2020 cohort of 699 patients with TB recruited during the COVID-19 pandemic. Between 2010 and 2020, the prevalence of the g2g-L2 strain almost doubled, nearly fully replacing the other co-circulating L2 strains. However, g2g-L2 infection was not associated with rs3130660 in this cohort. These data raise the possibility of a more dynamic landscape of interacting host, pathogen and environmental risk factors than previously expected for TB.
2024-03-30 | GSE262379 | GEO
Project description:Hematopoietic stem and progenitor cells (HSPCs) can give rise to all kinds of immune cells including neutrophils. Neutrophils are the first line of defense in the innate immune system with a short lifespan, due to which it is well-accepted that neutrophils have no immune memory. However, recent reports showed that the changes in HSPCs induced by primary stimulation could last a long time, which contributes to enhancing response to subsequent infection by generating more monocytes or macrophages equipped with stronger anti-bacterial function. Here, we used the reinfection mice model to reveal that primary infection could improve neutrophil-mediated host defense by training neutrophil progenitors in mammals, providing a new idea to enhance neutrophil number and improve neutrophil functions, which is pretty pivotal for patients with compromised or disordered immunity.
2025-04-03 | GSE145493 | GEO
Project description:Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global health threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a complementing strategy for infection treatment through targeting host immune mechanisms. However, the limited understanding of the host factors and their regulatory mechanisms involved in host immune defense against infections has impeded HDT development. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) elicits host protective immunity against Mtb. Mechanistically, TRIM27 enters host cell nucleus upon Mtb infection to function as a transcription activator of transcription factor EB (TFEB). TRIM27 binds to TFEB promoter and the TFEB transcription factor cAMP responsive element binding protein 1 (CREB1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity towards TFEB, eventually leading to autophagy activation and pathogen clearance. Thus, TRIM27 contributes to host anti-Mtb immunity and targeting TRIM27/CREB1/TFEB axis serves as a promising HDT-based TB treatment.
2024-07-03 | GSE237039 | GEO