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Transcriptomic signature for precise prediction of 3HP related systemic drug reaction for latent tuberculosis infection treatment: A prospective study

ABSTRACT: Transcriptomic signature for precise prediction of 3HP related systemic drug reaction for latent tuberculosis infection treatment: A prospective study

PROVIDER: PRJNA730527 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14569150_1.fastq.gz	Fastqsanger.gz
	SRR14569150_2.fastq.gz	Fastqsanger.gz
	SRR14569151_1.fastq.gz	Fastqsanger.gz
	SRR14569151_2.fastq.gz	Fastqsanger.gz
	SRR14569152_1.fastq.gz	Fastqsanger.gz

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Transcriptomic signature for precise prediction of 3HP related systemic drug reaction for latent tuberculosis infection treatment: A prospective study

Project description:Background: Systemic drug reaction (SDR) is a major safety concern of weekly rifapentine-based treatment (known as 3HP) for latent tuberculosis infection (LTBI). Understanding predictors of SDR and identifying risk subjects before treatment can improve public acceptance and cost-effective implement of LTBI program. Methods: We first prospectively recruited 187 subjects receiving 3HP and randomly selected a pilot cohort for generating whole-blood transcriptomic data. After integrating the hierarchical systems biology model (HiSBiM) and a therapy-biomarker pathway approach, candidate genes were obtained and evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Then, we developed interpretable machine learning models and established universal cut-off value (shapley additive explanations value) for each SDR prediction model. An independent cohort was used to evaluate the performance of these predictive models. Findings: Based on the transcriptomic profile of the pilot cohort, a total of 19 candidate genes were identified. Among them, six were sieved out by RT-qPCR results of a small number of samples from the training cohort. By applying the SHAP values of various combinations of the 6 gene expression signature, and the best model consisted of three genes, had an G-mean of 0.959, sensitivity of 0.972 and specificity of 0.947 for the joint of the two cohorts, and worked well across different subgroups.

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Transcriptomic Evaluation of Pyrococcus furiosus strains engineered to produce 3HP

Project description:A hybrid array setup containing WT Pyrococcus furiosus genes plus heterologous genes for engineered pathway producing 3HP from maltose and CO2 was used to study the impact of heterlogous pathway on native metabolic systems Four different experiments were run: 1) Pfu WT vs Pfu COM1; 2) Pfu COM1 vs MW56 (strain containing 3 heterologous genes from Metallosphaera sedula for production of 3HP); 3) Pfu COM1 vs MW76 at 72C before and after 3HP production; 4) MW76 at 72C before and after 3HP production at high agitation

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Project description:We studied components of TB immunity that remain impaired after cART in the lung compartment, versus those that are restored by concurrent 3 months of once weekly isoniazid and rifapentine (3HP) and cART in the rhesus macaque (RM) model of LTBI and Simian Immunodeficiency Virus (SIV) co-infection. Concurrent administration of cART+3HP did improve clinical and microbiological attributes of Mtb/SIV co-infection compared to cART-naïve or -untreated RMs. While RMs in the cART+3HP group exhibited significantly lower granuloma volumes after treatment, they, however, continued to harbor caseous granulomas with increased FDG uptake. cART only partially restores the constitution of CD4+ T cells to the lung compartment in co-infected macaques. Concurrent therapy did not further enhance the frequency of reconstituted CD4+ T cells in BAL and lung of Mtb/SIV co-infected RMs compared to cART, and treated animals continued to display incomplete reconstitution to the lung. Furthermore, the reconstituted CD4+ T cells in BAL and lung of cART+3HP treated RMs exhibited an increased frequencies of activated, exhausted and inflamed phenotype compared to LTBI RMs. cART+3HP failed to restore the effector memory CD4+ T cell population that was significantly reduced in pulmonary compartment post SIV co-infection. Concurrent therapy was associated with the induction of Type I IFN transcriptional signatures and led to increased Mtb-specific TH1/TH17 responses correlated with protection, but decreased Mtb-specific TNF responses, which could have a detrimental impact on long term protection.

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Project description:To investigate degradation genes in the 3HP degradation pathway, transcriptome sequencing was performed under culture conditions with and without 3HP as the carbon source. Overall, in the presence of 3HP as a sole carbon source, 384 genes were upregulated while 210 downregulated. Among them, we identified two 3HP degradation genes, GME_RS01260 encoding choline dehydrogenase (RefSeq. Accession: WP_009721523) and GME_RS01255 encoding CoA-acylating methylmalonate-semialdehyde dehydrogenase (RefSeq. Accession WP_009721522). Subsequently, transcriptome sequencing was performed under the culture condition with or without addition of PDO as a carbon source. Overall, 292 genes were upregulated while 285 downregulated with the addition of PDO. Among them, we identified an alcohol dehydrogenases AdhP (RefSeq. Accession: WP_039868491.1).

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