Gene expression profiling identifies candidate biomarkers for new latent tuberculosis infections. A cohort study

Abstract

Objective To determine the gene expression profile in individuals with new latent tuberculosis infection (LTBI), and to compare them with people with active tuberculosis (TB) and those exposed to TB but not infected. Design A prospective cohort study. Recruitment and follow-up were conducted between September 2016 to December 2018. Gene expression and data processing and analysis from April 2019 to April 2021. Setting Two male Colombian prisons. Participants 15 new tuberculin skin test (TST) converters (negative TST at baseline that became positive during follow-up), 11 people that continued with a negative TST after two years of follow-up, and 10 people with pulmonary ATB. Main outcome measures Gene expression profile using RNA sequencing from PBMC samples. The differential expression was assessed using the DESeq2 package in Bioconductor. Genes with |logFC| >1.0 and an adjusted p-value < 0.1 were differentially expressed. We analyzed the differences in the enrichment of KEGG pathways in each group using InterMiner. Results The gene expression was affected by the time of incarceration. We identified group-specific differentially expressed genes between the groups: 289 genes in people with a new LTBI and short incarceration (less than three months of incarceration), 117 in those with LTBI and long incarceration (one or more years of incarceration), 26 in ATB, and 276 in the exposed but non-infected individuals. Four pathways encompassed the largest number of down and up-regulated genes among individuals with LTBI and short incarceration: cytokine signaling, signal transduction, neutrophil degranulation, and innate immune system. In individuals with LTBI and long incarceration, the only enriched pathway within up-regulated genes was Emi1 phosphorylation. Conclusions Recent infection with MTB is associated with an identifiable RNA pattern related to innate immune system pathways that can be used to prioritize LTBI treatment for those at greatest risk for developing active TB.

Integrated sequence-based genomic, transcriptomic, and methylation characterization of the susceptibility to tuberculosis in monozygous twins

“…A number of genomic studies have recently been conducted to identify a set of genetic factors underlying susceptibility to TB including UBE3A [ 11 , 12 ], chromosome region 8q12–q13 [ 13 ], VDR, IL12, Il12RB1, INFG, MBL, DRB1, SFTPA1/2, and NRAMP1 [ [14] , [15] , [16] , [17] ], MCP1 [ 18 , 19 ], chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, chromosome 7p22-7p21 for TB [ 20 ], TST1 and TST2 [ 21 ], TNF1 [ 22 ], and CCL1 [ 23 ]. More specifically, genetic variants participating directly in human immunity such as interleukin (IL)-10, interferon (IFN)-γ, and nitric oxide synthase 2 play key roles in susceptibility to TB [ [24] , [25] , [26] , [27] , [28] ]. Additionally, previous studies have revealed the important roles of epigenetic modifications of a number of genes including NRAMP1, IFNG, NOS2A, VDR, ISG15, TACO, TLR1, TLR, IL18R1, PADI, DUSP14, and MBL, NLRP-3 , and MASP-2 in TB susceptibility [ [29] , [30] , [31] , [32] ].…”