Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has infected over 1.7 billion people worldwide and causes 1.4 million deaths annually. Recently, genome sequence analysis has allowed the reconstruction of Mycobacterium tuberculosis complex (MTBC) evolution, with the identification of seven phylogeographic lineages: four referred to as evolutionarily “ancient”, and three “modern”. The MTBC strains belonging to “modern” lineages appear to show enhanced virulence that may have warranted improved transmission in humans over ancient lineages through molecular mechanisms that remain to be fully characterized. To evaluate the impact of MTBC genetic diversity on the innate immune response, we analyzed intracellular bacterial replication, inflammatory cytokine levels, and autophagy response in human primary macrophages infected with MTBC clinical isolates belonging to the ancient lineages 1 and 5, and the modern lineage 4. We show that, when compared to ancient lineage 1 and 5, MTBC strains belonging to modern lineage 4 show a higher rate of replication, associated to a significant production of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and induction of a functional autophagy process. Interestingly, we found that the increased autophagic flux observed in macrophages infected with modern MTBC is due to an autocrine activity of the proinflammatory cytokine IL-1β, since autophagosome maturation is blocked by an interleukin-1 receptor antagonist. Unexpectedly, IL-1β-induced autophagy is not disadvantageous for the survival of modern Mtb strains, which reside within Rab5-positive phagosomal vesicles and avoid autophagosome engulfment. Altogether, these results suggest that autophagy triggered by inflammatory cytokines is compatible with a high rate of intracellular bacilli replication and may therefore contribute to the increased pathogenicity of the modern MTBC lineages.
Highlights
Mycobacterium tuberculosis (Mtb) emerged as a human pathogen 75–150 thousand years ago and spread by clonal expansion among human communities since giving rise to seven phylogeographic lineages which show a relatively limited genetic variability, consisting of largesequence polymorphisms (LSPs) and single-nucleotideOfficial journal of the Cell Death Differentiation AssociationRomagnoli et al Cell Death and Disease (2018)9:624 polymorphisms (SNPs)[1,2,3]
Mtb strains belonging to the modern lineage show a higher rate of intracellular replication To characterize the virulence properties of the selected Mtb complex (MTBC) strains, human monocyte-derived macrophages (MDM) were infected at multiplicity of infection (MOI) 1:1 and intracellular colony-forming unit (CFU) were determined at 4 h and 7 days post infection
Macrophages infected with different Mtb strains showed similar viability, as indicated by evaluating lactate dehydrogenase (LDH) release, indicating that cytotoxicity may not account for the observed differences of CFUs
Summary
Mycobacterium tuberculosis (Mtb) emerged as a human pathogen 75–150 thousand years ago and spread by clonal expansion among human communities since giving rise to seven phylogeographic lineages which show a relatively limited genetic variability, consisting of largesequence polymorphisms (LSPs) and single-nucleotideOfficial journal of the Cell Death Differentiation AssociationRomagnoli et al Cell Death and Disease (2018)9:624 polymorphisms (SNPs)[1,2,3]. Even human-adapted MTBC strains (Mtb) show phenotypic differences in terms of intracellular survival and transcriptional profile in macrophages[6,7,8,9,10] and virulence in mice[9,10]. The impact of these phenotypic differences between the humanadapted strains on TB disease and transmission remains elusive, the observed sympatric association between Mtb lineages and ethnic human groups supported the continuous adaptive process between Mtb and its host[11,12]
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