Whole-genome comparative analysis at the lineage/sublineage level discloses relationships between Mycobacterium tuberculosis genotype and clinical phenotype

Background Human tuberculosis (TB) caused by members of the Mycobacterium tuberculosis complex (MTBC) is the main cause of death among infectious diseases worldwide. Pulmonary TB (PTB) is the most common clinical phenotype of the disease, but some patients develop an extrapulmonary (EPTB) phenotype in which any organ or tissue can be affected. MTBC species include nine phylogenetic lineages, with some appearing globally and others being geographically restricted. EPTB can or not have pulmonary involvement, challenging its diagnosis when lungs are not implicated, thus causing an inadequate treatment. Finding evidence of a specific M. tuberculosis genetic background associated with EPTB is epidemiologically relevant due to the virulent and multidrug-resistant strains isolated from such cases. Until now, the studies conducted to establish associations between M. tuberculosis lineages and PTB/EPTB phenotypes have shown inconsistent results, which are attributed to the strain predominance from specific M. tuberculosis lineages/sublineages in the samples analyzed and the use of low-resolution phylogenetic tools that have impaired sublineage discrimination abilities. The present work elucidates the relationships between the MTBC strain lineages/sublineages and the clinical phenotypes of the disease as well as the antibiotic resistance of the strains. Methods To avoid biases, we retrieved the raw genomic reads (RGRs) of all (n = 245) the M. tuberculosis strains worldwide causing EPTB available in databases and an equally representative sample of the RGRs (n = 245) of PTB strains. A multiple alignment was constructed, and a robust maximum likelihood phylogeny based on single-nucleotide polymorphisms was generated, allowing effective strain lineage/sublineage assignment. Results A significant Odds Ratio (OR range: 1.8–8.1) association was found between EPTB and the 1.1.1, 1.2.1, 4.1.2.1 and ancestral Beijing sublineages. Additionally, a significant association between PTB with 4.3.1, 4.3.3, and 4.5 and Asian African 2 and Europe/Russia B0/W148 modern Beijing sublineages was found. We also observed a significant association of Lineage 3 strains with multidrug resistance (OR 3.8; 95% CI [1.1–13.6]), as well as between modern Beijing sublineages and antibiotic resistance (OR 4.3; 3.8–8.6). In this work, it was found that intralineage diversity can drive differences in the immune response that triggers the PTB/EPTB phenotype.

The role of Mycobacterium tuberculosis complex strain on apoptosis and necroptosis state of macrophages derived from active pulmonary tuberculosis patients

Objective The role of Mycobacterium tuberculosis complex (MTBC) strain in tuberculosis (TB) infection in human is still questioned. The aim of this study was to determine whether MTBC strain is associated with apoptosis and necroptosis by measuring the expression of specific signaling pathways components (Fas-associated protein with death domain (FADD) and receptor interacting protein 3 (RIP3)), as well as the level of apoptosis. Results We recruited 24 TB patients infected with M. tuberculosis Beijing strain and six patients with M. bovis BCG strain. Data indicated that those who infected with M. tuberculosis were more frequent to have severe lung damage than M. bovis (odds ratio [OR]: 7.60; 95% confidence interval [CI]: 1.07-54.09). M. tuberculosis infection was also associated with lower expression of FADD and lower apoptosis level of macrophage cells compared to M. bovis . No significant different of RIP3 between strain groups. In conclusion, M. tuberculosis Beijing strain is associated with severe pulmonary damage, inhibits FADD expression and reduces apoptosis level in macrophages derived from TB. This suggests that MTBC strain potentially be used as determinant of progressivity of disease and tissue damage in TB cases.

The role of Mycobacterium tuberculosis complex strain on apoptosis and necroptosis state of macrophages derived from active pulmonary tuberculosis patients

Objective The role of Mycobacterium tuberculosis complex (MTBC) strain in tuberculosis (TB) infection in human is still questioned. The aim of this study was to determine whether MTBC strain is associated with apoptosis and necroptosis by measuring the expression of specific signaling pathways components (Fas-associated protein with death domain (FADD) and receptor interacting protein 3 (RIP3)), as well as the level of apoptosis.Results We recruited 24 TB patients infected with M. tuberculosis Beijing strain and six patients with M. bovis BCG strain. Data indicated that those who infected with M. tuberculosis were more frequent to have severe lung damage than M. bovis (odds ratio [OR]: 7.60; 95% confidence interval [CI]: 1.07-54.09). M. tuberculosis infection was also associated with lower expression of FADD and lower apoptosis level of macrophage cells compared to M. bovis . No significant different of RIP3 between strain groups. In conclusion, M. tuberculosis Beijing strain is associated with severe pulmonary damage, inhibits FADD expression and reduces apoptosis level in macrophages derived from TB. This suggests that MTBC strain potentially be used as determinant of progressivity of disease and tissue damage in TB cases.

Experimental infection of cattle withMycobacterium tuberculosisisolates shows the attenuation of the human tubercle bacillus for cattle

TheMycobacterium tuberculosiscomplex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported thatM. tuberculosisH37Rv, a standard reference MTBC strain, is attenuated in cattle compared toMycobacterium bovis. However, asM. tuberculosisH37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation ofM. tuberculosisfor cattle by performing a bovine experimental infection with a recentM. tuberculosisisolate. Here we report infection of cattle usingM. bovisAF2122/97,M. tuberculosisH37Rv, andM. tuberculosisBTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that bothM. tuberculosisstrains caused reduced gross and histopathology in cattle compared toM. bovis. UsingM. tuberculosisH37Rv andM. bovisAF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation ofM. tuberculosisstrains for cattle, and emphasizes the potential of the bovine model as a ‘One Health’ approach to inform human TB biomarker development and post-exposure vaccine development.