@article{b45b5d881c244f829a29df2f996b5f46,
title = "Retention of EsxA in the Capsule-Like Layer of Mycobacterium tuberculosis Is Associated with Cytotoxicity and Is Counteracted by Lung Surfactant",
abstract = "Mycobacterium tuberculosis, the pathogen that causes tuberculosis, primarily infects macrophages but withstands the host cell's bactericidal effects. EsxA, also called virulence factor 6-kDa early secretory antigenic target (ESAT-6), is involved in phagosomal rupture and cell death. We provide confocal and electron microscopy data showing that M. tuberculosis bacteria grown without detergent retain EsxA on their surface. Lung surfactant has detergent-like properties and effectively strips off this surface-associated EsxA, which advocates a novel mechanism of lung surfactant-mediated defense against pathogens. Upon challenge of human macrophages with these M. tuberculosis bacilli, the amount of surface-associated EsxA rapidly declines in a phagocytosis-independent manner. Furthermore, M. tuberculosis bacteria cultivated under exclusion of detergent exert potent cytotoxic activity associated with bacterial growth. Together, this study suggests that the surface retention of EsxA contributes to the cytotoxicity of M. tuberculosis and highlights how cultivation conditions affect the experimental outcome.",
keywords = "ESAT-6, EsxA, Mycobacterium tuberculosis, cytotoxicity, human macrophage, lung surfactant, VIRULENCE, SECRETION, MEMBRANES, REVEALS, CYTOSOL, GROWTH, CFP-10",
author = "Johanna Raffetseder and Nino Iakobachvili and Vesa Loitto and Peters, {Peter J.} and Maria Lerm",
note = "Funding Information: This work was supported by the ZON-MW MKMD program (The Netherlands Organisation for Health Research and Development), the Swedish Research Council/ Swedish International Cooperation Agency (SIDA; 2012-3349 and 2015-02593), the Swedish Heart Lung/the Oskar II Jubilee Foundations (grant numbers 20130685 and 20150709), and the County Council of Ostergotland. Funding Information: The following reagent was obtained through the NIH Biodefense and Emerging Infections Research Resources Repository, NIAID, NIH: monoclonal anti-Mycobacterium tuberculosis LAM, clone CS-35 (produced in vitro), NR-13811. The following reagent was obtained through BEI Resources, NIAID, NIH: monoclonal anti-Mycobacterium tuberculosis GroEL2 (gene Rv0440), clone CS-44 (produced in vitro), NR-13813. Curosurf was a generous gift from Chiesi Pharma AB, Stockholm, Sweden. We acknowledge the members of the Microscopy Core Lab at M4I Maastricht University for their scientific and technological support regarding immunolabeling, with a special mention of Carmen L{\'o}pez-Iglesias and Hans Duimel. This work was supported by the ZON-MW MKMD program (The Netherlands Or-ganisation for Health Research and Development), the Swedish Research Council/ Swedish International Cooperation Agency (SIDA; 2012-3349 and 2015-02593), the Swedish Heart Lung/the Oskar II Jubilee Foundations (grant numbers 20130685 and 20150709), and the County Council of Ostergotland. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. J.R., N.I., V.L., P.J.P., and M.L. conceived of or designed the work; J.R., N.I., and V.L. collected the data; J.R., N.I., V.L., P.J.P., and M.L. performed data analysis, and interpretation; J.R., N.I., and M.L. drafted the article; J.R., N.I., V.L., P.J.P., and M.L. critically revised the article; and J.R., N.I., V.L., P.J.P., and M.L. gave final approval of the version to be published. Publisher Copyright: {\textcopyright} 2019 American Society for Microbiology. All Rights Reserved.",
year = "2019",
month = mar,
doi = "10.1128/IAI.00803-18",
language = "English",
volume = "87",
pages = "1--12",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "3",
}