Mycobacterium Tuberculosis

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Mycobacterium Tuberculosis The Mycobacterium marinum ESX-1 system mediates phagosomal permeabilization and type I interferon production via separable mechanisms Julia Lienarda, Esther Nobsa, Victoria Lovinsa,1, Elin Movertb, Christine Valfridssonb, and Fredric Carlssona,2 aDepartment of Biology, Section for Molecular Cell Biology, Lund University, 223 62 Lund, Sweden; and bDepartment of Experimental Medical Science, Section for Immunology, Lund University, 221 84 Lund, Sweden Edited by William R. Jacobs Jr, Albert Einstein College of Medicine, Bronx, NY, and approved November 27, 2019 (received for review July 8, 2019) Following mycobacterial entry into macrophages the ESX-1 type According to this model, ESX-1–mediated permeabilization of VII secretion system promotes phagosomal permeabilization and the phagosomal membrane causes passive leakage of extracel- type I IFN production, key features of tuberculosis pathogenesis. lular mycobacterial DNA into the host cell cytosol, where it is The current model states that the secreted substrate ESAT-6 is sensed by the cGAS/STING pathway to drive type I IFN pro- required for membrane permeabilization and that a subsequent duction (24, 26–29). Thus, it is widely believed that ESAT-6 is passive leakage of extracellular bacterial DNA into the host cell directly responsible for phagosomal permeabilization and a cytosol is sensed by the cyclic GMP-AMP synthase (cGAS) and subsequent default induction of type I IFN during mycobacterial stimulator of IFN genes (STING) pathway to induce type I IFN infection. production. We employed a collection of Mycobacterium marinum ESX-1 transposon mutants in a macrophage infection model and Results show that permeabilization of the phagosomal membrane does Analyses of ESAT-6 and CFP-10 Secretion Identify 3 Phenotypic Groups not require ESAT-6 secretion. Moreover, loss of membrane integ- among ESX-1–Deficient Mutants. To determine the genetic re- rity is insufficient to induce type I IFN production. Instead, type I quirements for ESX-1–mediated secretion of ESAT-6 and CFP- IFN production requires intact ESX-1 function and correlates with 10 we employed wild-type (WT) M. marinum and the ΔRD1 release of mitochondrial and nuclear host DNA into the cytosol, strain, lacking the entire RD1 region, as well as 9 previously indicating that ESX-1 affects host membrane integrity and DNA characterized isogenic transposon mutants deficient for individ- release via genetically separable mechanisms. These results sug- ual ESX-1–related genes (Fig. 1A). Cultures of these strains were gest a revised model for major aspects of ESX-1–mediated host fractionated into the secreted fraction (culture filtrate; CF), cell interactions and put focus on elucidating the mechanisms by envelope fraction (ENV), and cytosolic fraction (CYT), which which ESX-1 permeabilizes host membranes and induces the type were analyzed by Western blot (Fig. 1B). As controls we probed I IFN response, questions of importance for our basic understand- for Ag85B, which is secreted via the general secretory pathway, ing of mycobacterial pathogenesis and innate immune sensing. and the cell-associated protein GroEL. Although these controls did not distinguish between the envelope and cytosolic frac- mycobacterial pathogenesis | ESAT-6 secretion | membrane tions, they demonstrated similar loading and lack of unspecific permeabilization | mitochondrion | type I interferon leakage of cellular material into the CF, respectively (Fig. 1B). ycobacterium tuberculosis has an intracellular lifestyle and Significance Mis thought to reside primarily in host macrophages (1). During the 1970s the concept emerged that the bacterium propa- The mycobacterial ESX-1 type VII secretion system promotes gates exclusively within the phagosomal compartment, made pos- phagosomal rupture and type I IFN production, key features of sible by bacterial mechanisms to prevent phagosome maturation tuberculosis pathogenesis. It is currently believed that the secreted and acidification (2, 3). However, recent work has established that substrate ESAT-6 is required for phagosomal permeabilization and pathogenic mycobacteria can rupture the phagosomal membrane in that a subsequent leakage of bacterial DNA into the host cell cy- – an ESX-1 dependent manner to interact also with the cytosolic tosol triggers type I IFN. Our genetic analyses demonstrate that – compartment of infected cells in vitro (4 8) and in vivo (6, 9). ESX-1–mediated membrane permeabilization does not require The conserved ESX-1 secretion system is primarily encoded by ability to secrete ESAT-6 and is insufficient to induce type I IFN. “ genes within and adjacent to the chromosomal locus region of Instead, type I IFN production is associated with intact ESX-1 ” difference 1 (RD1), which is defined by a corresponding de- function and correlates with cytosolic release of host DNA. Thus, – letion in the Mycobacterium bovis bacillus Calmette Guérin ESX-1 affects host membrane integrity and induction of type I IFN – vaccine strain (10 12). Loss of RD1 is largely responsible for the via discrete mechanisms. Understanding these mechanisms may – attenuated phenotype of bacillus Calmette Guérin (13), and provide insight into how mycobacteria cause disease. genetic studies in both M. tuberculosis and M. marinum have confirmed a critical role for ESX-1 in intracellular growth and Author contributions: J.L. and F.C. designed research; J.L., E.N., V.L., E.M., C.V., and F.C. virulence (9, 14–17). ESAT-6 (EsxA) and CFP-10 (EsxB) are performed research; J.L., E.N., V.L., E.M., C.V., and F.C. analyzed data; and J.L. and F.C. encoded within RD1 and represent the two most well-known wrote the paper. substrates of ESX-1 (11). There is a substantial body of work— The authors declare no competing interest. based on both genetic (4, 5, 8, 10, 17) and biochemical (17–20) This article is a PNAS Direct Submission. approaches—suggesting that ESX-1–mediated permeabilization Published under the PNAS license. of the phagosomal membrane requires secretion of ESAT-6, 1Present address: Department of Dermatology, Perelman School of Medicine, University which has been ascribed membranolytic activity by functioning of Pennsylvania, Philadelphia, PA 19104. as a pore-forming protein (17, 20–22). Moreover, induction 2To whom correspondence may be addressed. Email: [email protected]. of the type I IFN response, which is exploited by mycobacteria This article contains supporting information online at https://www.pnas.org/lookup/suppl/ to promote infection (23–25), has been described as a direct doi:10.1073/pnas.1911646117/-/DCSupplemental. and inescapable consequence of phagosomal permeabilization. First published December 26, 2019. 1160–1166 | PNAS | January 14, 2020 | vol. 117 | no. 2 www.pnas.org/cgi/doi/10.1073/pnas.1911646117 Downloaded by guest on September 27, 2021 A BC D MICROBIOLOGY Fig. 1. Analyses of ESAT-6 and CFP-10 secretion delineate 3 phenotypic groups of ESX-1 mutants. (A) Schematic representation of the extended RD1 region of mycobacteria. Arrows represent individual genes with direction of transcription, and the colors highlight the transposon mutants used in this study (SI Appendix, Table S1). (B) M. marinum bacterial cultures of WT, ΔRD1, and the indicated transposon insertion mutants were fractionated into secreted (culture filtrates; CF), cell envelope (ENV), and cytosolic (CYT) fractions and analyzed by Western blot using specific antibodies. Ag85, a protein secreted by the general secretory pathway, and GroEL, a cell-associated protein, were used as controls. (C) Schematic representation of the 3 phenotypic groups of M. marinum strains identified based on their ability to secrete ESAT-6 and CFP-10. (D) C57BL/6 macrophages were infected with M. marinum at the indicated MOI, and in- tracellular bacterial growth was determined by cfu analyses at the indicate time points post infection. Phenotypic groups 1, 2, and 3 are indicated. Results (mean ± SD; n = 3) are representative of 3 independent experiments (2-way ANOVA, ****P < 0.0001). As expected, WT but not ΔRD1 produced and secreted ESAT-6 other mutants exhibited an intermediate phenotype irrespective and CFP-10 (Fig. 1B). Intriguingly, among the transposon mutants of their capacity to secrete ESAT-6 (Fig. 1D). The growth phe- we identified three principal phenotypic groups based on their ability notype for ESX-1 mutants in our system appeared stronger than to secrete ESAT-6 and CFP-10, respectively (Fig. 1 B and C). First, that observed in the M. tuberculosis system (15, 31), which might EspJ::tn and EspK::tn secreted both ESAT-6 and CFP-10, albeit at reflect the faster growth rate of M. marinum or potentially dif- reduced levels as compared to WT (Fig. 1B). Of note, these findings ferences in the ESX-1 systems from the two species (32). Nev- partly contrast with a previous study, in which the EspJ::tn and ertheless, the lack of correlation between ESX-1–mediated EspK::tn mutants were not observed to secrete ESAT-6 (10), a intracellular growth and ESAT-6 secretion in addition to a lack discrepancy that might be explained by differences in how the bac- of belonging to any phenotypic group made it of interest to terial fractions were generated. Second, EspE::tn, EspI::tn, and, to a further explore the role for ESAT-6 secretion in ESX-1–mediated lesser degree, EspB::tn secreted CFP-10 while being unable to se- functions. crete ESAT-6 (Fig. 1B), implying utility of these mutants as reagents to investigate the mechanism by which ESAT-6 piggybacks on CFP- ESX-1–Mediated Permeabilization of the Phagosomal Membrane Does 10 for its secretion (30). Third, EspG1::tn, EspH::tn, EccA1::tn, and Not Require ESAT-6 Secretion. After permeabilizing the phagosomal EccCb1::tn failed to secrete both ESAT-6 and CFP-10, a phenotype membrane and gaining access to the host cell cytosol, M. marinum associated with markedly reduced cytosolic levels of the substrates is able to induce actin tail formation at one of its polar ends (7). (Fig. 1B).
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