MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses

Yugang Li; Weihui Li; Zhiwei Xie; Hui Xu; Zheng-Guo He

doi:10.1016/j.jgg.2019.12.002

Volume 46 Issue 12

Dec. 2019

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2019 > 46(12): 575-589

PDF( 3832 KB)

MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses

doi: 10.1016/j.jgg.2019.12.002

a
National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
b
State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Life Science and Technology, Guangxi University, Nanning, 530004, China

More Information

Corresponding author: E-mail address: hezhengguo2019@163.com (Zheng-Guo He)
Received Date: 2019-11-05
Accepted Date: 2019-12-02
Rev Recd Date: 2019-11-28

Available Online: 2019-12-28

Publish Date: 2019-12-20

Abstract

Abstract

Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance. Phosphatidylinositol mannosides (PIMs) and their higher derivatives are important molecules implicated in host-pathogen interactions in the course of tuberculosis. However, the biosynthetic regulation of these specific lipids and its effect on the bacterial fate in the infected host remain unclear. Here, we show that a hypothetical M. tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation. MpbR inhibits the accumulation of acylated PIM lipids and triggers the mycobacterium to reduce the production of reactive oxygen species and NO during infection, which enhances the survival ofM. tuberculosis in macrophages. MpbR deletion reduces M. tuberculosis lung burdens and inflammation of infected mice. These findings provide new insights into the regulation of mycobacterial lipid metabolism and its correlation with pathogenesis of M. tuberculosis.
- Transcriptional factor,
- Lipid metabolism

FullText(HTML)

References(54)

References

[1]	Angala, S.K., Belardinelli, J.M., Huc-Claustre, E., Wheat, W.H., Jackson, M., 2014. The cell envelope glycoconjugates of Mycobacterium tuberculosis. Crit. Rev. Biochem. Mol. Biol. 49, 361-399.
[2]	Biswas, R.K., Dutta, D., Tripathi, A., Feng, Y., Banerjee, M., Singh, B.N., 2013. Identification and characterization of Rv0494: a fatty acid-responsive protein of the GntR/FadR family from Mycobacterium tuberculosis. Microbiology 159, 913-923.
[3]	Boldrin, F., Ventura, M., Degiacomi, G., Ravishankar, S., Sala, C., Svetlikova, Z., Ambady, A., Dhar, N., Kordulakova, J., Zhang, M., Serafini, A., Vishwas, K.G., Kolly, G.S., Kumar, N., Palu, G., Guerin, M.E., Mikusova, K., Cole, S.T., Manganelli, R., 2014. The phosphatidyl-myo-inositol mannosyltransferase PimA is essential for Mycobacterium tuberculosis growth in vitro and in vivo. J. Bacteriol. 196, 3441-3451.
[4]	Cambier, C.J., Takaki, K.K., Larson, R.P., Hernandez, R.E., Tobin, D.M., Urdahl, K.B., Cosma, C.L., Ramakrishnan, L., 2014. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218-222.
[5]	Chen, J.M., German, G.J., Alexander, D.C., Ren, H., Tan, T., Liu, J., 2006. Roles of Lsr2 in colony morphology and biofilm formation of Mycobacterium smegmatis. J. Bacteriol. 188, 633-641.
[6]	Choi, J.A., Lim, Y.J., Cho, S.N., Lee, J.H., Jeong, J.A., Kim, E.J., Park, J.B., Kim, S.H., Park, H.S., Kim, H.J., Song, C.H., 2013. Mycobacterial HBHA induces endoplasmic reticulum stress-mediated apoptosis through the generation of reactive oxygen species and cytosolic Ca2+ in murine macrophage RAW 264.7 cells. Cell Death Dis. 4:e957.
[7]	Cole, S.T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S.V., Eiglmeier, K., Gas, S., Barry, C.E. 3rd., Tekaia, F., Badcock, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Feltwell, T., Gentles, S., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Krogh, A., McLean, J., Moule, S., Murphy, L., Oliver, K., Osborne, J., Quail, M.A., Rajandream, M.A., Rogers, J., Rutter, S., Seeger, K., Skelton, J., Squares, R., Squares, S., Sulston, J.E., Taylor, K., Whitehead, S., Barrell, B.G., 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537-544.
[8]	Doz, E., Rose, S., Court, N., Front, S., Vasseur, V., Charron, S., Gilleron, M., Puzo, G., Fremaux, I., Delneste, Y., Erard, F., Ryffel, B., Martin, O.R., Quesniaux, V.F., 2009. Mycobacterial phosphatidylinositol mannosides negatively regulate host Toll-like receptor 4, MyD88-dependent proinflammatory cytokines, and TRIF-dependent co-stimulatory molecule expression. J. Biol. Chem. 284, 23187-23196.
[9]	Drage, M.G., Tsai, H.C., Pecora, N.D., Cheng, T.Y., Arida, A.R., Shukla, S., Rojas, R.E., Seshadri, C., Moody, D.B., Boom, W.H., Sacchettini, J.C., Harding, C.V., 2010. Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nat. Struct. Mol. Biol. 17, 1088-1095.
[10]	Fan, L., Wu, X., Jin, C., Li, F., Xiong, S., Dong Y., 2018. MptpB promotes Mycobacteria survival by inhibiting the expression of inflammatory mediators and cell apoptosis in macrophages. Front. Cell. Infect. Microbiol. 8, 171.
[11]	Fischer, K., Scotet, E., Niemeyer, M., Koebernick, H., Zerrahn, J., Maillet, S., Hurwitz, R., Kursar, M., Bonneville, M., Kaufmann, S.H., Schaible, U.E., 2004. Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells. Proc. Natl. Acad. Sci. U. S. A. 101, 10685-10690.
[12]	Fukuda, T., Matsumura, T., Ato, M., Hamasaki, M., Nishiuchi, Y., Murakami, Y., Maeda, Y., Yoshimori, T., Matsumoto, S., Kobayashi, K., Kinoshita, T., Morita, Y.S., 2013. Critical roles for lipomannan and lipoarabinomannan in cell wall integrity of mycobacteria and pathogenesis of tuberculosis. MBio 4, e00472-12.
[13]	Gao, C.H., Yang, M., He, Z.G., 2012. Characterization of a novel ArsR-like regulator encoded by Rv2034 in Mycobacterium tuberculosis. PLoS One 7, e36255.
[14]	Gaur, R.L., Ren, K., Blumenthal, A., Bhamidi, S., Gibbs, S., Jackson, M., Zare, R.N., Ehrt, S., Ernst, J.D., Banaei, N., 2015. LprG-mediated surface expression of lipoarabinomannan is essential for virulence of Mycobacterium tuberculosis. PLoS Pathog. 11, e1005336.
[15]	Gilleron, M., Ronet, C., Mempel, M., Monsarrat, B., Gachelin, G., Puzo, G., 2001. Acylation state of the phosphatidylinositol mannosides from Mycobacterium bovis bacillus Calmette Guerin and ability to induce granuloma and recruit natural killer T cells. J. Biol. Chem. 276, 34896-34904.
[16]	Gilleron, M., Quesniaux, V.F., Puzo, G., 2003. Acylation state of the phosphatidylinositol hexamannosides from Mycobacterium bovis bacillus Calmette Guerin and Mycobacterium tuberculosis H37Rv and its implication in Toll-like receptor response. J. Biol. Chem. 278, 29880-29889.
[17]	Glass, L.N., Swapna, G., Chavadi, S.S., Tufariello, J.M., Mi, K., Drumm, J.E., Lam, T.T., Zhu, G., Zhan, C., Vilcheze, C., Arcos, J., Chen, Y., Bi, L., Mehta, S., Porcelli, S.A., Almo, S.C., Yeh, S.R., Jacobs, W.R. Jr., Torrelles, J.B., Chan, J., 2017. Mycobacterium tuberculosis universal stress protein Rv2623 interacts with the putative ATP binding cassette (ABC) transporter Rv1747 to regulate mycobacterial growth. PLoS Pathog. 13, e1006515.
[18]	Gonzalo Asensio, J., Maia, C., Ferrer, N.L., Barilone, N., Laval, F., Soto, C.Y., Winter, N., Daffe, M., Gicquel, B., Martin, C., Jackson, M., 2006. The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis. J. Biol. Chem. 2813, 1313-1316.
[19]	Goren, M.B., 1984. Biosynthesis and structures of phospholipids and sulfatides, in: Kubica, G.P., Wayne, L.G. (Eds.), The Mycobacteria. Marcel Dekker Inc., New York, pp. 370-415.
[20]	Guerin, M.E., Kaur, D., Somashekar, B.S., Gibbs, S., Gest, P., Chatterjee, D., Brennan, P.J., Jackson, M., 2009. New Insights into the Early Steps of Phosphatidylinositol Mannoside Biosynthesis in Mycobacteria: PimB′ is an essential enzyme of Mycobacterium smegmatis. J. Biol. Chem. 284, 25687-25696.
[21]	Guerin, M.E., Kordulakova, J., Alzari, P.M., Brennan, P.J., Jackson, M., 2010. Molecular basis of phosphatidyl-myo-inositol mannoside biosynthesis and regulation in mycobacteria. J. Biol. Chem. 285, 33577-33583.
[22]	Howard, N.C., Marin, N.D., Ahmed, M., Rosa, B.A., Martin, J., Bambouskova, M., Sergushichev, A., Loginicheva, E., Kurepina, N., Rangel-Moreno, J., Chen, L., Kreiswirth, B.N., Klein, R.S., Balada-Llasat, J.M., Torrelles, J.B., Amarasinghe, G.K., Mitreva, M., Artyomov, M.N., Hsu, F.F., Mathema, B., Khader, S.A., 2018. Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes. Nat. Microbiol. 3, 1327.
[23]	Hsu, F.F., Turk, J., Owens, R.M., Rhoades, E.R., Russell, D.G., 2007. Structural characterization of phosphatidyl-myo-inositol mannosides from Mycobacterium bovis Bacillus Calmette Guerin by multiple-stage quadrupole ion-trap mass spectrometry with electrospray ionization. II. Monoacyl-and diacyl-PIMs. J. Am. Soc. Mass Spectrom. 18, 479-492.
[24]	Jankute, M., Grover, S., Birch, H.L., Besra, G.S., 2014. Genetics of mycobacterial arabinogalactan and lipoarabinomannan assembly. Microbiol. Spectr. 2, MGM2-0013-2013.
[25]	Layre, E., Sweet, L., Hong, S., Madigan, C.A., Desjardins, D., Young, D.C., Cheng, T.Y., Annand, J.W., Kim, K., Shamputa, I.C., McConnell, M.J., Debono, C.A., Behar, S.M., Minnaard, A.J., Murray, M., Barry, C.E. 3rd., Matsunaga, I., Moody, D.B., 2011. A comparative lipidomics platform for chemotaxonomic analysis of Mycobacterium tuberculosis. Chem. Biol. 18, 1537-1549.
[26]	Lee, H.J., Ko, H.J., Song, D.K., Jung, Y.J., 2018. Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A-Phosphatidylinositol 3 Kinase-p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages. Front. Immunol. 9, 920.
[27]	Li, W., He, Z.G., 2012. LtmA, a novel cyclic di-GMP-responsive activator, broadly regulates the expression of lipid transport and metabolism genes in Mycobacterium smegmatis. Nucleic Acids Res. 40, 11292-11307.
[28]	Li, W., Li, M., Hu, L., Zhu, J., Xie, Z., Chen, J., He, Z.G., 2018. HpoR, a novel c-di-GMP effective transcription factor, links the second messenger’s regulatory function to the mycobacterial antioxidant defense. Nucleic Acids Res. 46, 3595-3611.
[29]	Liu, X.X., Shen, M.J., Liu, W.B., Ye, B.C., 2018. Transcriptional and post-translational regulation of AccD6 in Mycobacterium smegmatis. FEMS Microbiol. Lett. 365, doi: 10.1093/femsle/fny074.
[30]	Liu, Y., Wang, H., Cui, T., Zhou, X., Jia, Y., Zhang, H., He, Z.G., 2016. NapM, a new nucleoid-associated protein, broadly regulates gene expression and affects mycobacterial resistance to anti-tuberculosis drugs. Mol. Microbiol. 101, 167-181.
[31]	Liu, Y.G., Chen, Y., 2007. High-efficiency thermal asymmetric interlaced PCR for amplification of unknown flanking sequences. Biotechniques 43, 649-656.
[32]	Mondino, S., Gago, G., Gramajo, H., 2013. Transcriptional regulation of fatty acid biosynthesis in mycobacteria. Mol. Microbiol. 89, 372-387.
[33]	Morita, Y.S., Sena, C.B., Waller, R.F., Kurokawa, K., Sernee, M.F., Nakatani, F., Haites, R.E., Billman-Jacobe, H., McConville, M.J., Maeda, Y., Kinoshita, T., 2006. PimE is a polyprenol-phosphate-mannose-dependent mannosyltransferase that transfers the fifth mannose of phosphatidylinositol mannoside in mycobacteria. J. Biol. Chem. 281, 25143-25155.
[34]	Ojha, A., Anand, M., Bhatt, A., Kremer, L., Jacobs, W.R. Jr., Hatfull, G.F., 2005. GroEL1: a dedicated chaperone involved in mycolic acid biosynthesis during biofilm formation in mycobacteria. Cell 123, 861-873.
[35]	Ojha, A.K., Baughn, A.D., Sambandan, D., Hsu, T., Trivelli, X., Guerardel, Y., Alahari, A., Kremer, L., Jacobs, W.R. Jr., Hatfull, G.F., 2008. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol. Microbiol. 69, 164-174.
[36]	Parish, T., Liu, J., Nikaido, H., Stoker, N.G., 1997. A Mycobacterium smegmatis mutant with a defective inositol monophosphate phosphatase gene homolog has altered cell envelope permeability. J. Bacteriol. 179, 7827-7833.
[37]	Quigley, J., Hughitt, V.K., Velikovsky, C.A., Mariuzza, R.A., El-Sayed, N.M, Briken, V., 2017. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of Mycobacterium tuberculosis. MBio 8, e00148-17.
[38]	Recht, J., Martinez, A., Torello, S., Kolter, R., 2000. Genetic Analysis of Sliding Motility in Mycobacterium smegmatis. J. Bacteriol. 182, 4348-4351.
[39]	Salzman, V., Mondino, S., Sala, C., Cole, S.T., Gago, G., Gramajo, H., 2010. Transcriptional regulation of lipid homeostasis in mycobacteria. Mol. Microbiol. 78, 64-77.
[40]	Sartain, M.J., Dick, D.L., Rithner, C.D., Crick, D.C., Belisle, J.T., 2011. Lipidomic analyses of Mycobacterium tuberculosis based on accurate mass measurements and the novel “Mtb LipidDB”. J. Lipid Res. 52, 861-872.
[41]	Sassetti, C.M., Boyd, D.H., Rubin, E.J., 2001. Comprehensive identification of conditionally essential genes in mycobacteria. Proc. Natl. Acad. Sci. U. S. A. 98, 12712-12717.
[42]	Shukla, S., Richardson, E.T., Athman, J.J., Shi, L., Wearsch, P.A., McDonald, D., Banaei, N., Boom, W.H., Jackson, M., Harding, C.V., 2014 Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion. PLoS Pathog. 10, e1004471.
[43]	Sprott, G.D., Dicaire, C.J., Gurnani, K., Sad, S., Krishnan, L., 2004. Activation of dendritic cells by liposomes prepared from phosphatidylinositol mannosides from Mycobacterium bovis bacillus Calmette-Guerin and adjuvant activity in vivo. Infect. Immun. 72, 5235-5246.
[44]	Srinivasan, L., Gurses, S.A., Hurley, B.E., Miller, J.L., Karakousis, P.C., Briken, V., 2016. Identification of a transcription factor that regulates host cell exit and virulence of Mycobacterium tuberculosis. PLoS Pathog. 12, e1005652.
[45]	Stover, C.K., de la Cruz, V.F., Fuerst, T.R., Burlein, J.E., Benson, L.A., Bennett, L.T., Bansal, G.P., Young, J.F., Lee, M.H., Hatfull, G.F., Snapper, S.B., Barletta, R.G., Jacobs Jr, W.R., Bloom, B.R., 1991. New use of BCG for recombinant vaccines. Nature 351, 456-460.
[46]	Torrelles, J.B., Azad, A.K., Schlesinger, L.S., 2006. Fine discrimination in the recognition of individual species of phosphatidyl-myo-inositol mannosides from Mycobacterium tuberculosis by C-type lectin pattern recognition receptors. J. Immunol. 177, 1805-1816.
[47]	Toyonaga, K., Torigoe, S., Motomura, Y., Kamichi, T., Hayashi, J.M., Morita, Y.S., Noguchi, N., Chuma, Y., Kiyohara, H., Matsuo, K., Tanaka, H., Nakagawa, Y., Sakuma, T., Ohmuraya, M., Yamamoto, T., Umemura, M., Matsuzaki, G., Yoshikai, Y., Yano, I., Miyamoto, T., Yamasaki, S., 2016. C-type lectin receptor DCAR recognizes mycobacterial phosphatidyl-inositol mannosides to promote a Th1 response during infection. Immunity 45, 1245-1257.
[48]	Vir, P., Gupta, D., Agarwal, R., Verma, I., 2014. Immunomodulation of alveolar epithelial cells by Mycobacterium tuberculosis phosphatidylinositol mannosides results in apoptosis. APMIS. 122, 268-282.
[49]	Walters, S.B., Dubnau, E., Kolesnikova, I., Laval, F., Daffe, M., Smith, I., 2006. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol. Microbiol. 60, 312-330.
[50]	Wang, J., Li, B.X., Ge, P.P., Li, J., Wang, Q., Gao, G.F., Qiu, X.B., Liu, C.H., 2015. Mycobacterium tuberculosis suppresses innate immunity by coopting the host ubiquitin system. Nat. Immunol. 16, 237-245.
[51]	Wang, Y., Huang, Y., Xue, C., He, Y., He, Z.G., 2011. ClpR protein-like regulator specifically recognizes RecA protein-independent promoter motif and broadly regulates expression of DNA damage-inducible genes in mycobacteria. J. Biol. Chem. 286, 31159-31167.
[52]	World Health Organization (WHO), 2018. Global Tuberculosis Report 2018. World Health Organization, Geneva.
[53]	Wright, C.C., Hsu, F.F., Arnett, E., Dunaj, J.L., Davidson, P.M., Pacheco, S.A., Harriff, M.J., Lewinsohn, D.M., Schlesinger, L.S., Purdy, G.E., 2017. The Mycobacterium tuberculosis MmpL11 cell wall lipid transporter is important for biofilm formation, intracellular growth, and nonreplicating persistence. Infect. Immun. 85, e00131-17.
[54]	Zhang, L., Li, W., He, Z.G., 2013. DarR, a TetR-like transcriptional factor, is a cyclic di-AMP-responsive repressor in Mycobacterium smegmatis. J. Biol. Chem. 288, 3085-3096.