Histone acetylome-wide association study on tuberculosis infection
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ABSTRACT:
PROVIDER: EGAS00001003118 | EGA |
REPOSITORIES: EGA
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Project description:Mycobacterium tuberculosis (Mtb) causes a wide spectrum of human disease ranging from asymptomatic latent infection to severe host pathology, but it remains unclear how Mtb influence on leukocyte gene expression differs between disease states. We assessed mRNA expression in blood monocytes and granulocytes by next-generation sequencing in healthy controls and patients with active tuberculosis infection. We found genome-wide gene expression changes in granulocyte and monocyte which correlated with disease severity.
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Project description:Tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection remains a huge global public health problem. One striking characteristic of Mtb is its ability to adapt to hypoxia, and thus ensuing transition to dormant state for persistent infection, but how the hypoxia responses of Mtb is regulated remains largely unknown. Here, we performed a quantitative acetylome analysis to compare the acetylation profile of Mtb under aeration and hypoxia, and showed that 377 acetylation sites in 269 proteins of Mtb were significantly change under hypoxia. Especially, deacetylation of Dormancy Survival Regulator (DosR) at K182 promoted the hypoxia response of Mtb and enhanced transcription of DosR-targeted genes. Mechanistically, recombinant DosRK182R protein demonstrated enhanced DNA-binding activity in comparison with DosRK182Q protein. Moreover, Rv0998 was identified as an acetyltransferase that mediates the acetylation of DosR at K182. Deletion of Rv0998 also promoted the adaption of Mtb to hypoxia and transcription of DosR-targeted genes. Mice infected with Mtb strain containing acetylation-defective DosRK182R or lacking Rv0998 had much lower bacterial counts, and less severe histopathological impairments compared with those infected with the wild-type strain. Our findings suggest that hypoxia induces the deacetylation of DosR, which in turn increases its DNA binding ability to promote the transcription of target genes, allowing Mtbto transit to dormancy under hypoxia.
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Project description:Tuberculosis (TB) is one of the deadliest infectious disorders in the world. To effectively TB manage, an essential step is to gain insight into the lineage of Mycobacterium tuberculosis (MTB) strains and the distribution of drug resistance. Although the Campania region is declared a cluster area for the infection, to contribute to the effort to understand TB evolution and transmission, still poorly known, we have generated a dataset of 159 genomes of MTB strains, from Campania region collected during 2018-2021, obtained from the analysis of whole genome sequence data. The results show that the most frequent MTB lineage is the 4 according for 129 strains (81.11%). Regarding drug resistance, 139 strains (87.4%) were classified as multi susceptible, while the remaining 20 (12.58%) showed drug resistance. Among the drug-resistance strains, 8 were isoniazid-resistant MTB (HR-MTB), 7 were resistant only to one antibiotic (3 were resistant only to ethambutol and 3 isolate to streptomycin while one isolate showed resistance to fluoroquinolones), 4 multidrug-resistant MTB, while only one was classified as pre-extensively drug-resistant MTB (pre-XDR). This dataset expands the existing available knowledge on drug resistance and evolution of MTB, contributing to further TB-related genomics studies to improve the management of TB infection.
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2017-06-06 | PXD006389 | Pride
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.
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Project description:Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes tuberculosis (TB), an infectious disease that inflicts major health and economic costs around the world. Mtb encounters diverse environments during its lifecycle and responds to these changes by reprogramming its transcriptional output. However, the mechanisms and regulation of Mtb transcription remains poorly understood. In this work, we simultaneously determine the 5' and 3' ends of individual RNA molecules in Mtb cells using the SEnd-seq method, which enables us to profile the Mtb transcriptome at high resolution. Unexpectedly, we find that most Mtb transcripts are incomplete, with their 5' ends aligned at transcription start sites and 3' ends located 200-500 nucleotides downstream. Using native elongating transcript sequencing, we show that these short RNAs are mainly associated with paused RNA polymerases (RNAPs) rather than products of premature termination. We further show that the high propensity of Mtb RNAP to pause early in transcription is dependent on the binding of the sigma factor. Finally, we show that a translating ribosome promotes transcription elongation, suggesting a role for transcription-translation coupling in Mtb gene expression. In sum, our findings depict a mycobacterial transcriptome that prominently features incomplete transcripts resulting from RNAP pausing. We propose that the pausing phase constitutes an important transcriptional checkpoint in Mtb that allows the bacterium to adapt to new environments and could be exploited for TB therapeutics.
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Project description:Mycobacterium tuberculosis (Mtb) is one of the most successful pathogens in human history and remains the second leading cause of death from an infectious agent worldwide. The major reason of Mtb success principally relies on its ability to perfectly adapt to the host, by establishing latent infection and evading from the control driven by immune system. Accordingly, both innate and adaptive immune responses are required to control TB progression and pathogenesis and in particular dendritic cells (DC), as professional antigen presenting cells, are one of the major cellular effectors of the anti-mycobacterial response. In this context, we performed a microarray analysis to characterize the de-regulation of cellular miRNAs during Mtb infection of human DC. Human DC were prepared from human peripheral blood mononuclear cells of anonymous healthy blood donors and infected with Mtb for 3, 8 and 24 hours. This data set contains the global miRNA expression profiling in uninfected and Mtb-infected DC cultures to identify altered signature of miRNAs potentially implicated in Mtb-mediated immune evasion strategies.
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