INTEGRATIVE MULTI-OMICS REVEAL A TWO-ANALYTE BLOOD-BASED SIGNATURE FOR TB DIAGNOSIS IN ADVANCED HIV

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 diagnose 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 ART with CD4 cell counts <50 cells/uL. Twenty-three cases of incident TB were site-matched with 32 controls to identify miRNAs, cytokines/chemokines, and metabolites 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 in cases relative to controls (p<0.05). Differentially altered metabolite analysis showed no significant alterations in 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). 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 a severely immunosuppressed PLWH study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166557 | GEO | 2021/06/30

REPOSITORIES: GEO