Biological signatures of infectious disease resistance: Deciphering immunological mechanisms of resistance to tuberculosis (TB) by combining host genetics and immuno-transcriptomics

Abstract

Understanding the biological signatures for resistance to Mycobacterium tuberculosis (Mtb) in a unique group termed resisters (RSTR) is crucial. Despite extensive exposure to the pathogen, these individuals remain uninfected, highlighting elusive yet critical natural resistance pathways. In efforts to elucidate the molecular mechanisms behind the unique resistance to Mtb, we hypothesized that unique gene expression patterns in alveolar macrophages might explain this resistance phenomenon. Utilizing immuno-transcriptomic profiling and single nucleotide polymorphism (SNP) array genotyping, we analyzed alveolar macrophage samples from an observational cohort in Uganda, comparing RSTR and latent TB infection (LTBI) (N=49 participants). Differential gene expression analysis revealed elevated BMAL1 expression in RSTR relative to LTBI (false discovery rate [FDR], <0.25). Gene set enrichment analyses (GSEA) identified multiple gene sets differentiating RSTR and LTBI alveolar macrophages. The only significantly enriched gene set in RSTR compared to LTBI was the E2F biological pathway encoding cell cycle-related targets (false discovery rate [FDR], <0.2). Intriguingly, these findings allude to a potential convergence of these pathways with autophagy, a crucial defense mechanism against Mtb infection. This novel intersection between autophagy and circadian rhythm processes active in RSTRs point to a new avenue for host directed therapeutic interventions against tuberculosis (TB).