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Integrative Multi-Omics Reveals Serum Markers of Tuberculosis in Advanced HIV.
- Source :
-
Frontiers in immunology [Front Immunol] 2021 Jun 08; Vol. 12, pp. 676980. Date of Electronic Publication: 2021 Jun 08 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Tuberculosis (TB) accounts for disproportionate morbidity and mortality among persons living with HIV (PLWH). Conventional methods of TB diagnosis, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in PLWH. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in very advanced HIV. We conducted a case-control study leveraging REMEMBER, a multi-country, open-label randomized controlled trial comparing 4-drug empiric standard TB treatment with isoniazid preventive therapy in PLWH initiating antiretroviral therapy (ART) with CD4 cell counts <50 cells/μL. Twenty-three cases of incident TB were site-matched with 32 controls to identify microRNAs (miRNAs), metabolites, and cytokines/chemokines, associated with the development of newly diagnosed TB in PLWH. Differentially expressed miRNA analysis revealed 11 altered miRNAs with a fold change higher than 1.4 or lower than -1.4 in cases relative to controls (p<0.05). Our analysis revealed no differentially abundant metabolites between cases and controls. We found higher TNFα and IP-10/CXCL10 in cases (p=0.011, p=0.0005), and higher MDC/CCL22 in controls (p=0.0072). A decision-tree algorithm identified gamma-glutamylthreonine and hsa-miR-215-5p as the optimal variables to classify incident TB cases (AUC 0.965; 95% CI 0.925-1.000). hsa-miR-215-5p, which targets genes in the TGF-β signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases. To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed PLWH.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors NK.<br /> (Copyright © 2021 Krishnan, Queiroz, Gupta, Gupte, Bisson, Kumwenda, Naidoo, Mohapi, Mave, Mngqibisa, Lama, Hosseinipour, Andrade and Karakousis.)
- Subjects :
- AIDS-Related Opportunistic Infections drug therapy
AIDS-Related Opportunistic Infections virology
Adult
Anti-Retroviral Agents therapeutic use
Antitubercular Agents therapeutic use
Biomarkers blood
Case-Control Studies
Chemokines blood
Drug Therapy, Combination
Female
High-Throughput Nucleotide Sequencing
Humans
Isoniazid therapeutic use
Male
Metabolome
Metabolomics methods
MicroRNAs blood
MicroRNAs genetics
Mycobacterium tuberculosis isolation & purification
Treatment Outcome
Tuberculosis, Pulmonary diagnosis
Tuberculosis, Pulmonary drug therapy
AIDS-Related Opportunistic Infections complications
HIV
Mycobacterium tuberculosis genetics
Tuberculosis, Pulmonary blood
Tuberculosis, Pulmonary complications
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 34168648
- Full Text :
- https://doi.org/10.3389/fimmu.2021.676980