TY - JOUR
T1 - Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production
AU - Sousa, Jeremy
AU - Cá, Baltazar
AU - Maceiras, Ana Raquel
AU - Simões-Costa, Luisa
AU - Fonseca, Kaori L
AU - Fernandes, Ana Isabel
AU - Ramos, Angélica
AU - Carvalho, Teresa
AU - Barros, Leandro
AU - Magalhães, Carlos
AU - Chiner-Oms, Álvaro
AU - Machado, Henrique
AU - Veiga, Maria Isabel
AU - Singh, Albel
AU - Pereira, Rui
AU - Amorim, António
AU - Vieira, Jorge
AU - Vieira, Cristina P
AU - Bhatt, Apoorva
AU - Rodrigues, Fernando
AU - Rodrigues, Pedro N S
AU - Gagneux, Sebastien
AU - Castro, António Gil
AU - Guimarães, João Tiago
AU - Bastos, Helder Novais
AU - Osório, Nuno S
AU - Comas, Iñaki
AU - Saraiva, Margarida
PY - 2020/4/23
Y1 - 2020/4/23
N2 - 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.
AB - 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.
KW - Animals
KW - Bacterial Proteins/genetics
KW - Cells, Cultured
KW - Cytokines/metabolism
KW - Cytosol/immunology
KW - Female
KW - Genome, Bacterial/genetics
KW - Humans
KW - Immune Evasion
KW - Immunomodulation
KW - Inflammasomes/immunology
KW - Interleukin-1beta/metabolism
KW - Macrophages/immunology
KW - Male
KW - Mice
KW - Mutation
KW - Mycobacterium tuberculosis/classification
KW - Phylogeny
KW - Polymorphism, Single Nucleotide
KW - Signal Transduction/immunology
KW - Tuberculosis, Pulmonary/immunology
KW - Virulence/genetics
UR - http://www.scopus.com/inward/record.url?scp=85083842157&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-15832-6
DO - 10.1038/s41467-020-15832-6
M3 - Article
C2 - 32327653
SN - 2041-1723
VL - 11
SP - 1949
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1949
ER -