Association between human genomes and mycobacterial genomes contributes to severity and transmissibility of pulmonary tuberculosis.

Pulmonary tuberculosis (PTB) remains a major infectious disease globally. This study aimed to identify determinants of Mycobacterium tuberculosis (MTB) transmission clustering, treatment outcome, and pulmonary cavitation by simultaneously analyzing host and pathogen genomic data. Whole-genome sequencing of 1,960 MTB isolates identified four major lineages (L1-L4). Host population stratification by principal component analysis of genome-wide single nucleotide polymorphisms (SNPs) classified 899 patients (70%) into a genetically homogeneous main group for genome-wide association study (GWAS). Multivariate regression demonstrated that MTB lineage was the primary determinant of transmission clustering, rifampicin resistance was the dominant predictor of unfavorable treatment outcome, and host genetic group was independently associated with pulmonary cavitation. GWAS identified novel loci in collectin subfamily member 10 (COLEC10), CTNNA3, and long intergenic non-coding RNA 2775 (LINC02775) associated with clustering, treatment outcome, and cavitation, respectively, with the association of COLEC10 also found in the remaining group of patients. These findings highlight the importance of integrating bacterial and human genomic analyses to understand tuberculosis host-pathogen interaction.