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A5542 - Peripheral Blood Circular RNAs as Novel Diagnostic Biomarker in Active Pulmonary Tuberculosis
Author Block: T. Zhou1, W. Gu2, Z. Qian3; 1Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, United States, 2School of Biological Sciences and Medical Engineering, Southeast University, Nanjing, China, 3Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, China.
Rationale: Circular RNAs (circRNAs) are a class of novel RNAs that are formed by back-splicing. Aberrant expression of many circRNAs has been implicated in human diseases. Notably, circRNAs are enriched and stable in whole blood, platelets, and exosomes. These features make circRNAs in human peripheral blood good candidates for diagnostic or prognostic biomarkers. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Recently, several studies have developed blood transcriptomic signatures to distinguish active pulmonary TB patients from other pulmonary disease cohorts and healthy controls and predicted the risk of developing active TB. However, the expression of mRNA transcripts in peripheral blood can be obscured by blood collection procedures, which may slow down the process of their clinical applications. Therefore, new markers in the peripheral blood are needed to facilitate the early diagnosis and treatment of active pulmonary TB. In this study, we investigated the potential of using circRNAs in peripheral blood mononuclear cells (PBMCs) as biomarkers for pulmonary TB diagnosis. Methods: We sequenced the rRNA-depleted RNA-seq libraries of human PBMC samples in the discovery cohort, including subjects with active pulmonary TB and age- and gender-matched healthy controls. The expression of both mRNAs and circRNAs was simultaneously quantified by our recently published framework, Sailfish-cir. Results: First, we demonstrated that circRNAs are widely expressed in human PBMCs and that many are abundant enough to be detected. Second, we found that the magnitude of PBMC circRNAs in TB patients was higher than that in the paired healthy controls. Under the assumption that the function of a given circRNA could be associated with the known function of its parental gene, we performed a novel pathway-based analysis. We found that, compared with host linear transcripts, the circRNAs within several Kyoto Encyclopedia of Genes and Genomes physiological pathways are disproportionately upregulated in active TB patients, including “Cytokine-cytokine receptor interaction”, “Chemokine signaling pathway”, “Neurotrophin signaling pathway”, and “Bacterial invasion of epithelial cells”. Based on the differentially expressed circRNAs within these pathways, we developed a PBMC circRNA-based molecular signature differentiating active TB patients from healthy controls. Using qRT-PCR, we validated the classification power of the PBMC circRNA signature in an independent cohort with an accuracy of 94%. Conclusions: Our results suggest that PBMC circRNAs are potentially reliable marker molecules in TB diagnosis.