Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

Jeremy Sousa, Baltazar Cá, Ana Raquel Maceiras, Luisa Simões-Costa, Kaori L Fonseca, Ana Isabel Fernandes, Angélica Ramos, Teresa Carvalho, Leandro Barros, Carlos Magalhães, Álvaro Chiner-Oms, Henrique Machado, Maria Isabel Veiga, Albel Singh, Rui Pereira, António Amorim, Jorge Vieira, Cristina P Vieira, Apoorva Bhatt, Fernando RodriguesPedro N S Rodrigues, Sebastien Gagneux, António Gil Castro, João Tiago Guimarães, Helder Novais Bastos, Nuno S Osório, Iñaki Comas, Margarida Saraiva

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1β is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1β production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

Original languageEnglish
Pages (from-to)1949
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Apr 2020

Keywords

  • Animals
  • Bacterial Proteins/genetics
  • Cells, Cultured
  • Cytokines/metabolism
  • Cytosol/immunology
  • Female
  • Genome, Bacterial/genetics
  • Humans
  • Immune Evasion
  • Immunomodulation
  • Inflammasomes/immunology
  • Interleukin-1beta/metabolism
  • Macrophages/immunology
  • Male
  • Mice
  • Mutation
  • Mycobacterium tuberculosis/classification
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Signal Transduction/immunology
  • Tuberculosis, Pulmonary/immunology
  • Virulence/genetics

Fingerprint

Dive into the research topics of 'Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production'. Together they form a unique fingerprint.

Cite this