Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages

• Published in: PLoS pathogens Vol. 7; no. 3; p. e1001307
• Main Authors: Portevin, Damien, Gagneux, Sébastien, Comas, Iñaki, Young, Douglas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2011; Public Library of Science (PLoS)
• Subjects: Animals; Biological Evolution; Bone Marrow Cells - metabolism; Causes of; Chemokines - biosynthesis; Chemokines - blood; Cytokines; Cytokines - biosynthesis; Cytokines - blood; Development and progression; Evolutionary Biology/Microbial Evolution and Genomics; Experiments; Flow cytometry; Genetic aspects; Genetic diversity; Genetic Variation; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Host-Pathogen Interactions; Humans; Immune response; Immune system; Immunity, Innate; Immunology/Innate Immunity; Infectious Diseases/Bacterial Infections; Macrophages; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred BALB C; Microbiology/Cellular Microbiology and Pathogenesis; Migration; Monocytes - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Phylogenetics; Phylogeny; Physiological aspects; Principal components analysis; Statistical analysis; Studies; Tuberculosis; Tuberculosis - microbiology; Tuberculosis - transmission; Switzerland; China; Africa
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1001307

The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC). Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed for different pro-inflammatory cytokines and chemokines, and was conserved across multiple human donors. Although each major phylogenetic lineage of MTBC included strains inducing a range of cytokine responses, we found that overall inflammatory phenotypes differed significantly across lineages. In particular, comparison of evolutionarily modern lineages demonstrated a significant skewing towards lower early inflammatory response. The differential response to ancient and modern lineages observed using GM-CSF derived macrophages was also observed in autologous monocyte-derived dendritic cells and murine bone marrow-derived macrophages, but not in human unfractionated peripheral blood mononuclear cells. We hypothesize that the reduced immune responses to modern lineages contribute to more rapid disease progression and transmission, which might be a selective advantage in the context of expanding human populations. In addition to the lineage effects, the large strain-to-strain variation in innate immune responses elicited by MTBC will need to be considered in tuberculosis vaccine development.