Integrative Multi-Omics Reveals Serum Markers of Tuberculosis in Advanced HIV

Front Immunol. 2021 Jun 8;12:676980. doi: 10.3389/fimmu.2021.676980. eCollection 2021.

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.

Keywords: HIV; biomarker; metabolomics; microRNA; multi-omics; tuberculosis.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS-Related Opportunistic Infections / complications*
  • 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
  • HIV*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Isoniazid / therapeutic use
  • Male
  • Metabolome
  • Metabolomics / methods
  • MicroRNAs / blood
  • MicroRNAs / genetics
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / isolation & purification
  • Treatment Outcome
  • Tuberculosis, Pulmonary / blood*
  • Tuberculosis, Pulmonary / complications*
  • Tuberculosis, Pulmonary / diagnosis
  • Tuberculosis, Pulmonary / drug therapy

Substances

  • Anti-Retroviral Agents
  • Antitubercular Agents
  • Biomarkers
  • Chemokines
  • MIRN215 microRNA, human
  • MicroRNAs
  • Isoniazid