Tuberculosis severity and its association with pathogen phylogeny and properties

A striking feature of tuberculosis (TB) is the variability of infection outcomes. The heterogeneity observed has been classically attributed to environmental and host determinants. However, recent studies uncovering Mycobacterium tuberculosis complex (MTBC) genomic diversity have shown the potential importance of pathogen-related factors. Nonetheless, the role of this variability in the clinical setting is still underappreciated. In the present work, 193 patients without known predictor or precipitator TB factors were selected from a cohort of 681 pulmonary TB cases, and stratified into TB severity groups. The MTBC infecting strains from these patients were isolated and genotyped using single nucleotide polymorphisms (SNPs) as stable genetic markers to define the different phylogenetic lineages and sublineages. SNP-typing revealed that the large majority (n= 94, 96.9%) of the infecting isolates belong to Lineage 4 (L4 or Euro-American) and that the sublineage LAM (Latin American-Mediterranean) represented 72.2% of the L4 isolates. Disease severity was not exclusively related to any specific phylogenetic taxa. In conclusion, we show a highly homogeneous phylogenetic composition of MTBC in a population of north of Portugal, where L4 and LAM sublineage dominate. Furthermore, mutations implicated in disease severity are not associated with lineage defining variability, but could be related to recent microevolution events within host. The methods used in this study appear well suited to monitor the molecular epidemiology regarding MTBC population structure.