Dataset Information

A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

ABSTRACT: Background: Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV. Methods: We enrolled 30 patients with advanced HIV (CD4 <100 cells/mm³) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda (n = 33; 18 with TB and 15 without). Transcriptomic profiling and machine learning algorithms identified an optimal gene signature for TB classification. Receiver operating characteristic analysis was used to assess performance. Results: Among 565 differentially expressed genes identified for TB, 40 were shared across India and Uganda cohorts. Common upregulated pathways reflect Toll-like receptor cascades and neutrophil degranulation. The machine-learning decision-tree algorithm selected gene expression values from RAB20 and INSL3 as most informative for TB classification. The signature accurately classified TB in discovery cohorts (India AUC 0.95 and Uganda AUC 1.0; p < 0.001); accuracy was fair in external validation cohorts. Conclusions: Expression values of RAB20 and INSL3 genes in peripheral blood compose a biosignature that accurately classified TB status among patients with advanced HIV in two geographically distinct cohorts. The functional analysis suggests pathways previously reported in TB pathogenesis.

SUBMITTER: Kulkarni V

PROVIDER: S-EPMC7937880 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

Kulkarni Vandana V Queiroz Artur T L ATL Sangle Shashi S Kagal Anju A Salvi Sonali S Gupta Amita A Ellner Jerrold J Kadam Dileep D Rolla Valeria C VC Andrade Bruno B BB Salgame Padmini P Mave Vidya V

Frontiers in immunology 20210222

Background: Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV. Methods: We enrolled 30 patients with advanced HIV (CD4 <100 cells/mm3) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda (n = 33; 18 with TB and 15 without). Transcriptomic profiling and mac ...[more]

PMID: 33692804

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Project description:IntroductionTuberculosis (TB) is a common opportunistic infection among people living with HIV. Diagnostic tests such as culture, Xpert-MTB-RIF, and ULTRA have low sensitivity in paucibacillary TB disease; a blood biomarker could improve TB diagnostic capabilities. We assessed soluble factors to identify biomarkers associated with TB among persons with advanced HIV.MethodsA case-control (1:1) study was conducted, with participants from Rio de Janeiro and Manaus, Brazil. People living with HIV presenting with CD4 count ≤100 cells/mm3 were eligible to participate. Cases had culture-confirmed TB (N=15) (positive for Mycobacterium tuberculosis [Mtb]); controls had HIV-infection only (N=15). Study visits included baseline, month 2 and end of TB therapy, during which samples of peripheral blood were obtained. A panel containing 29 biomarkers including cytokines, chemokines and growth factors was utilized to assess candidate biomarkers using Luminex technology in cryopreserved EDTA plasma samples. We used neural network analysis, based on machine learning, to identify biomarkers (single or in combination) that best distinguished cases from controls. Additional multi-dimensional analyses provided detailed profiling of the systemic inflammatory environment in cases and controls.ResultsMedian CD4 count and HIV-1 RNA load values were similar between groups at all timepoints. Persons with TB had lower body mass index (BMI) (median=19.6, Interquartile Range [IQR]=18.6-22.3) than controls (23.7; IQR: 21.8 = 25.5, p=0.004). TB coinfection was also associated with increased frequency of other comorbidities. The overall profile of plasma cytokines, chemokines and growth factors were distinct between the study groups at all timepoints. Plasma concentrations of IL-15 and IL-10 were on average lower in TB cases than in controls. When used in combination, such markers were able to discriminate between TB cases and controls with the highest degree of accuracy at each study timepoint.ConclusionAmong persons with advanced HIV, plasma concentrations of IL-15 and IL-10 can be used in combination to identify TB disease regardless of time on anti-TB treatment.

Project description:HIV-infected individuals are at high risk of tuberculosis disease and those with prior tuberculosis episodes are at even higher risk of disease recurrence. A non-sputum biomarker that identifies individuals at highest tuberculosis risk would allow targeted microbiological testing and appropriate treatment and also guide need for prolonged therapy. We determined the utility of a previously developed whole blood transcriptomic correlate of risk (COR) signature for (1) predicting incident recurrent tuberculosis, (2) tuberculosis diagnosis and (3) its potential utility for tuberculosis treatment monitoring in HIV-infected individuals. We retrieved cryopreserved blood specimens from three previously completed clinical studies and measured the COR signature by quantitative microfluidic real-time-PCR. The signature differentiated recurrent tuberculosis progressors from non-progressors within 3 months of diagnosis with an area under the Receiver-operating characteristic (ROC) curve (AUC) of 0.72 (95% confidence interval (CI), 0.58-0.85) amongst HIV-infected individuals on antiretroviral therapy (ART). Twenty-five of 43 progressors (58%) were asymptomatic at microbiological diagnosis and thus had subclinical disease. The signature showed excellent diagnostic discrimination between HIV-uninfected tuberculosis cases and controls (AUC 0.97; 95%CI 0.94-1). Performance was lower in HIV-infected individuals (AUC 0.83; 95%CI 0.81-0.96) and signature scores were directly associated with HIV viral loads. Tuberculosis treatment response in HIV-infected individuals on ART with a new recurrent tuberculosis diagnosis was also assessed. Signature scores decreased significantly during treatment. However, pre-treatment scores could not differentiate between those who became sputum negative before and after 2 months. Direct application of the unmodified blood transcriptomic COR signature detected subclinical and active tuberculosis by blind validation in HIV-infected individuals. However, prognostic performance for recurrent tuberculosis, and performance as diagnostic and as treatment monitoring tool in HIV-infected persons was inferior to published results from HIV-negative cohorts. Our results suggest that performance of transcriptomic signatures comprising interferon stimulated genes are negatively affected in HIV-infected individuals, especially in those with incompletely suppressed viral loads.

Project description:Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.

Dataset Information

A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

Publications

A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

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