Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

Abstract

Rationale: Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown.Objectives: To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses.Methods: Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors. We subjected these strains to wholegenome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility. Measurements and Main Results:We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis.Conclusions: In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro.

Update in Tuberculosis and Nontuberculous Mycobacteria 2017

“…Two studies in the Journal offered advances in this field. Nebenzahl-Guimares and colleagues used a tuberculosis registry and strain collection in the Netherlands to identify mycobacterial genetic markers associated with increased transmissibility, and to examine whether these lead to altered in vitro immune responses (40).…”

Genotypic clustering does not imply recent tuberculosis transmission in a high prevalence setting: A genomic epidemiology study in Lima, Peru

“…A few prior studies have characterized bacterial genetic factors that contributed to increased transmissibility. 24,27,50 We add to this literature by identifying five cluster defining SNPs to be under positive selection in a large TB genomic dataset. One of these SNPs ( esxV S23L) is a member of the ESAT-6 family of secreted proteins, some of which have been shown to be involved in host-pathogen interactions and may thus have contributed to increased transmissibility.…”

“…18–20 Factors known to contribute to DR-TB transmission include delays in diagnosis and treatment, 21 host factors like age, and immune status, 22–24 as well as bacterial factors such as fitness and immunogenicity characteristics. 25–27 It is well recognized that Mycobacterium tuberculosis (MTB) strains with the same DR conferring mutations have a range of fitness. 28–30 However, to date few molecular fitness determinants have been characterized and seldom in the context of high transmissibility.…”

Genotypic Clustering Does Not Imply Recent Tuberculosis Transmission in a High Prevalence Setting: A Genomic Epidemiology Study in Lima, Peru

“…Our study had five patients with a particularly high PTP above the highest reported value of 3•9 52 , potentially contributing to transmission in the population we studied. A few prior studies have characterized bacterial genetic factors that contributed to increased transmissibility 24,67,68 . We add to this literature by identifying five cluster defining SNPs to be under positive selection in a large TB genomic dataset.…”

“…Factors known to contribute to DR-TB transmission include delays in diagnosis and treatment 21 , host factors (e.g. age, immune status [22][23][24], as well as bacterial factors such as fitness and immunogenicity characteristics [25][26][27] . It is well recognized that Mycobacterium tuberculosis (MTB) strains with the same DR-conferring mutations have a range of fitness [28][29][30] .…”