Y blood RNA signature RISK4LEP predicts leprosy years before clinical onset

Background: Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is often late-or misdiag-nosed leading to irreversible disabilities. Blood transcriptomic biomarkers that prospectively predict those who progress to leprosy (progressors) would allow early diagnosis, better treatment outcomes and facilitate interventions aimed at stopping bacterial transmission. To identify potential risk signatures of leprosy, we collected whole blood of household contacts (HC, n=5,352) of leprosy patients, including individuals who were diagnosed with leprosy 4-61 months after sample collection.Methods: We investigated differential gene expression (DGE) by RNA-Seq between progressors before pres-ence of symptoms (n=40) and HC (n=40), as well as longitudinal DGE within each progressor. A prospective leprosy signature was identified using a machine learning approach (Random Forest) and validated using reverse transcription quantitative PCR (RT-qPCR). Findings: Although no significant intra-individual longitudinal variation within leprosy progressors was iden-tified, 1,613 genes were differentially expressed in progressors before diagnosis compared to HC. We identi-fied a 13-gene prospective risk signature with an Area Under the Curve (AUC) of 95.2%. Validation of this RNA-Seq signature in an additional set of progressors (n=43) and HC (n=43) by RT-qPCR, resulted ina final 4 -gene signature, designated RISK4LEP (MT-ND2, REX1BD, TPGS1, UBC) (AUC=86.4%).Interpretation: This study identifies for the first time a prospective transcriptional risk signature in blood pre-dicting development of leprosy 4 to 61 months before clinical diagnosis. Assessment of this signature in con-tacts of leprosy patients can function as an adjunct diagnostic tool to target implementation of interventions to restrain leprosy development. (C) 2021 The Author(s). Published by Elsevier B.V.