Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation

Abstract

Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection.

AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection

“…Twin studies estimate the heritability (proportion of the variation in susceptibility attributed to genetics) to be as high as 80% but estimates vary over a substantial range [ 12 ]. The vast majority of candidate SNPs likely affects regulatory mechanisms, leading to a growing consensus that gene regulation plays a prominent role, particularly in genes subject to evolutionary selection pressures [ 7 – 9 , 13 ].…”

Human genetics of mycobacterial disease

“…This led to the identification of 318 genes that were impacted by cis -eQTL in either stimulated or non-stimulated samples (FDR of 0.01), while 66 of these genes displayed eQTL only in one condition (response eQTL) directly demonstrating the interaction of host genetic background and pathogen exposure. Interestingly, the same study also showed that both eQTL and response-eQTL are targeted by positive selection (Manry et al 2017 ).…”

“…Recently, the impact of genetic variation on the human response to M. leprae was demonstrated by an eQTL study of whole blood cells in the presence and absence of M. leprae antigen (Manry et al 2017 ). Of particular interest was the identification of genetic regulators of host gene expression levels that depended on the presence of M. leprae .…”

Polymorphisms in mitochondrial ribosomal protein S5 (MRPS5) are associated with leprosy risk in Chinese

“…A differential expression analysis of mRNA was conducted to investigate the transcription alterations of target genes during M. leprae infection using the available data of Gene Expression Omnibus (GEO). Two datasets were downloaded and reanalyzed: (1) dataset GEO: GSE100853, a genome-wide search for expression quantitative trait loci before and after stimulation with sonicate of M. leprae in whole-blood from 51 unrelated individuals from Vietnam with borderline leprosy [39]; (2) dataset GEO: GSE74481, which included the mRNA profiles PLOS NEGLECTED TROPICAL DISEASES in leprosy skin lesions of 24 individuals with multibacillary leprosy including 10 BB, 10 BL, and 4 LL, 20 individuals with paucibacillary leprosy consisting of 10 TT and 10 BT, 14 individuals with type I reaction, and 9 individuals with type II reaction, and normal skin biopsies of nine healthy individuals used as controls [40].…”