Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1β-induced autophagy article

Alessandra Romagnoli, Elisa Petruccioli, Ivana Palucci, Serena Camassa, Elisabetta Carata, Linda Petrone, Stefania Mariano, Michela Sali, Luciana Dini, Enrico Girardi, Giovanni Delogu, Delia Goletti, Gian Maria Fimia

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number624
JournalCell Death and Disease
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1β-induced autophagy article'. Together they form a unique fingerprint.

  • Cite this

    Romagnoli, A., Petruccioli, E., Palucci, I., Camassa, S., Carata, E., Petrone, L., Mariano, S., Sali, M., Dini, L., Girardi, E., Delogu, G., Goletti, D., & Fimia, G. M. (2018). Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1β-induced autophagy article. Cell Death and Disease, 9(6), [624]. https://doi.org/10.1038/s41419-018-0640-8