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Mycobacterium tuberculosis PE25/PPE41 protein complex induces activation and maturation of dendritic cells and drives Th2-biased immune responses

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Abstract

Mycobacterium tuberculosis evades innate host immune responses by parasitizing macrophages and causes significant morbidity and mortality around the world. A mycobacterial antigen that can activate dendritic cells (DCs) and elicit effective host innate immune responses will be vital to the development of an effective TB vaccine. The M. tuberculosis genes PE25/PPE41 encode proteins which have been associated with evasion of the host immune response. We constructed a PE25/PPE41 complex gene via splicing by overlapping extension and expressed it successfully in E. coli. We investigated whether this protein complex could interact with DCs to induce effective host immune responses. The PE25/PPE41 protein complex induced maturation of isolated mouse DCs in vitro, increasing expression of cell surface markers (CD80, CD86 and MHC-II), thereby promoting Th2 polarization via secretion of pro-inflammatory cytokines IL-4 and IL-10. In addition, PE25/PPE41 protein complex-activated DCs induced proliferation of mouse CD4+ and CD8+ T cells, and a strong humoral response in immunized mice. The sera of five TB patients were also highly reactive to this antigen. These findings suggest that interaction of the PE25/PPE41 protein complex with DCs may be of great immunological significance.

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References

  1. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG (2002) Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 185(8):1197–1202. doi:10.1086/339818

    Article  PubMed  Google Scholar 

  2. Davis JM, Ramakrishnan L (2009) The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136(1):37–49. doi:10.1016/j.cell.2008.11.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dolin PJ, Raviglione MC, Kochi A (1994) Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Organ 72(2):213–220

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, III, 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 MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393(6685):537–544. doi:10.1038/31159

  5. Strong M, Sawaya MR, Wang S, Phillips M, Cascio D, Eisenberg D (2006) Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103(21):8060–8065. doi:10.1073/pnas.0602606103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Williams EP, Lee JH, Bishai WR, Colantuoni C, Karakousis PC (2007) Mycobacterium tuberculosis SigF regulates genes encoding cell wall-associated proteins and directly regulates the transcriptional regulatory gene phoY1. J Bacteriol 189(11):4234–4242. doi:10.1128/JB.00201-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nair S, Ramaswamy PA, Ghosh S, Joshi DC, Pathak N, Siddiqui I, Sharma P, Hasnain SE, Mande SC, Mukhopadhyay S (2009) The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage. J Immunol 183(10):6269–6281. doi:10.4049/jimmunol.0901367

    Article  CAS  PubMed  Google Scholar 

  8. Okkels LM, Brock I, Follmann F, Agger EM, Arend SM, Ottenhoff TH, Oftung F, Rosenkrands I, Andersen P (2003) PPE protein (Rv3873) from DNA segment RD1 of Mycobacterium tuberculosis: strong recognition of both specific T-cell epitopes and epitopes conserved within the PPE family. Infect Immun 71(11):6116–6123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Narayana Y, Joshi B, Katoch VM, Mishra KC, Balaji KN (2007) Differential B-cell responses are induced by Mycobacterium tuberculosis PE antigens Rv1169c, Rv0978c, and Rv1818c. CVI 14(10):1334–1341. doi:10.1128/CVI.00181-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tundup S, Akhter Y, Thiagarajan D, Hasnain SE (2006) Clusters of PE and PPE genes of Mycobacterium tuberculosis are organized in operons: evidence that PE Rv2431c is co-transcribed with PPE Rv2430c and their gene products interact with each other. FEBS Lett 580(5):1285–1293. doi:10.1016/j.febslet.2006.01.042

    Article  CAS  PubMed  Google Scholar 

  11. Tundup S, Pathak N, Ramanadham M, Mukhopadhyay S, Murthy KJ, Ehtesham NZ, Hasnain SE (2008) The co-operonic PE25/PPE41 protein complex of Mycobacterium tuberculosis elicits increased humoral and cell mediated immune response. PLoS ONE 3(10):e3586. doi:10.1371/journal.pone.0003586

    Article  PubMed  PubMed Central  Google Scholar 

  12. Demangel C, Britton WJ (2000) Interaction of dendritic cells with mycobacteria: where the action starts. Immunol Cell Biol 78(4):318–324. doi:10.1046/j.1440-1711.2000.00935.x

    Article  CAS  PubMed  Google Scholar 

  13. Pieters J (2008) Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3(6):399–407. doi:10.1016/j.chom.2008.05.006

    Article  CAS  PubMed  Google Scholar 

  14. Byun EH, Kim WS, Shin AR, Kim JS, Whang J, Won CJ, Choi Y, Kim SY, Koh WJ, Kim HJ, Shin SJ (2012) Rv0315, a novel immunostimulatory antigen of Mycobacterium tuberculosis, activates dendritic cells and drives Th1 immune responses. J Mol Med 90(3):285–298. doi:10.1007/s00109-011-0819-2

    Article  CAS  PubMed  Google Scholar 

  15. Byun EH, Kim WS, Kim JS, Jung ID, Park YM, Kim HJ, Cho SN, Shin SJ (2012) Mycobacterium tuberculosis Rv0577, a novel TLR2 agonist, induces maturation of dendritic cells and drives Th1 immune response. FASEB J 26(6):2695–2711. doi:10.1096/fj.11-199588

    Article  CAS  PubMed  Google Scholar 

  16. Bansal K, Sinha AY, Ghorpade DS, Togarsimalemath SK, Patil SA, Kaveri SV, Balaji KN, Bayry J (2010) Src homology 3-interacting domain of Rv1917c of Mycobacterium tuberculosis induces selective maturation of human dendritic cells by regulating PI3K-MAPK-NF-kappaB signaling and drives Th2 immune responses. J Biol Chem 285(47):36511–36522. doi:10.1074/jbc.M110.158055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Steinman RM (2007) Dendritic cells: understanding immunogenicity. Eur J Immunol 37(Suppl 1):S53–S60. doi:10.1002/eji.200737400

    Article  CAS  PubMed  Google Scholar 

  18. Steinman RM, Inaba K (1999) Myeloid dendritic cells. J Leukoc Biol 66(2):205–208

    CAS  PubMed  Google Scholar 

  19. Guo S, Bao L, Qin ZF, Shi XX (2010) The CFP-10/ESAT-6 complex of Mycobacterium tuberculosis potentiates the activation of murine macrophages involvement of IFN-gamma signaling. Med Microbiol Immunol 199(2):129–137. doi:10.1007/s00430-010-0146-1

    Article  CAS  PubMed  Google Scholar 

  20. Hickman SP, Chan J, Salgame P (2002) Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization. J Immunol 168(9):4636–4642

    Article  CAS  PubMed  Google Scholar 

  21. Zhao N, Wang X, Zhang Y, Gu Q, Huang F, Zheng W, Li Z (2013) Gestational zinc deficiency impairs humoral and cellular immune responses to hepatitis B vaccination in offspring mice. PLoS ONE 8(9):e73461. doi:10.1371/journal.pone.0073461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou ZD, Zeng QL, Zheng Y, Zhang JB, Chen HY, Lu DQ, Shao CS, Xia DJ (2008) Surface markers and functions of human dendritic cells exposed to mobile phone 1800 MHz electromagnetic fields. J Zhejiang Univ Med Sci 37(1):29–33

    CAS  Google Scholar 

  23. Deng YH, Sun Z, Yang XL, Bao L (2010) Improved immunogenicity of recombinant Mycobacterium bovis bacillus Calmette–Guerin strains expressing fusion protein Ag85A-ESAT-6 of Mycobacterium tuberculosis. Scand J Immunol 72(4):332–338. doi:10.1111/j.1365-3083.2010.02444.x

    Article  CAS  PubMed  Google Scholar 

  24. Chakhaiyar P, Nagalakshmi Y, Aruna B, Murthy KJR, Katoch VM, Hasnain SE (2004) Regions of high antigenicity within the hypothetical PPE major polymorphic tandem repeat open-reading frame, Rv2608, show a differential humoral response and a low T cell response in various categories of patients with tuberculosis. J Infect Dis 190(7):1237–1244. doi:10.1086/423938

    Article  CAS  PubMed  Google Scholar 

  25. Feng G, Jiang Q, Xia M, Lu Y, Qiu W, Zhao D, Lu L, Peng G, Wang Y (2013) Enhanced immune response and protective effects of nano-chitosan-based DNA vaccine encoding T cell epitopes of Esat-6 and FL against Mycobacterium tuberculosis infection. PLoS ONE 8(4):e61135. doi:10.1371/journal.pone.0061135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Flynn JL, Chan J (2001) Tuberculosis: latency and reactivation. Infect Immun 69(7):4195–4201. doi:10.1128/IAI.69.7.4195-4201.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lienhardt C, Azzurri A, Amedei A, Fielding K, Sillah J, Sow OY, Bah B, Benagiano M, Diallo A, Manetti R, Manneh K, Gustafson P, Bennett S, D’Elios MM, McAdam K, Del Prete G (2002) Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo. Eur J Immunol 32(6):1605–1613. doi:10.1002/1521-4141(200206)32:6<1605:Aid-Immu1605>3.0.Co;2-6

    Article  CAS  PubMed  Google Scholar 

  28. Jiao XN, Lo-Man R, Guermonprez P, Fiette L, Deriaud E, Burgaud S, Gicquel B, Winter N, Leclerc C (2002) Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. J Immunol 168(3):1294–1301

    Article  CAS  PubMed  Google Scholar 

  29. Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, Lagrange PH, Gicquel B, Neyrolles O (2003) DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 197(1):121–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Balaji KN, Goyal G, Narayana Y, Srinivas M, Chaturvedi R, Mohammad S (2007) Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells. Microbes Infect 9(3):271–281. doi:10.1016/j.micinf.2006.11.013

    Article  CAS  PubMed  Google Scholar 

  31. Rhoades E, Hsu F, Torrelles JB, Turk J, Chatterjee D, Russell DG (2003) Identification and macrophage-activating activity of glycolipids released from intracellular Mycobacterium bovis BCG. Mol Microbiol 48(4):875–888

    Article  CAS  PubMed  Google Scholar 

  32. Deng W, Li W, Zeng J, Zhao Q, Li C, Zhao Y, Xie J (2014) Mycobacterium tuberculosis PPE family protein Rv1808 manipulates cytokines profile via co-activation of MAPK and NF-kappaB signaling pathways. Cell Physiol Biochem 33(2):273–288. doi:10.1159/000356668

    Article  CAS  PubMed  Google Scholar 

  33. Choudhary RK, Pullakhandam R, Ehtesham NZ, Hasnain SE (2004) Expression and characterization of Rv2430c, a novel immunodominant antigen of Mycobacterium tuberculosis. Protein Expr Purif 36(2):249–253. doi:10.1016/j.pep.2004.03.016

    Article  CAS  PubMed  Google Scholar 

  34. Tundup S, Mohareer K, Hasnain SE (2014) Mycobacterium tuberculosis PE25/PPE41 protein complex induces necrosis in macrophages: role in virulence and disease reactivation? FEBS Open Bio 4:822–828. doi:10.1016/j.fob.2014.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Welin A, Eklund D, Stendahl O, Lerm M (2011) Human macrophages infected with a high burden of ESAT-6-expressing M. tuberculosis undergo caspase-1- and cathepsin B-independent necrosis. PLoS ONE 6(5):e20302. doi:10.1371/journal.pone.0020302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hossain MM, Norazmi MN (2013) Pattern recognition receptors and cytokines in Mycobacterium tuberculosis infection–the double-edged sword? Bio Med Res Int 2013:179174. doi:10.1155/2013/179174

    Google Scholar 

  37. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M, Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y (2003) Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197(1):7–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bodnar KA, Serbina NV, Flynn JL (2001) Fate of Mycobacterium tuberculosis within murine dendritic cells. Infect Immun 69(2):800–809. doi:10.1128/Iai.69.2.800-809.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sim YS, Kim SY, Kim EJ, Shin SJ, Koh WJ (2012) Impaired expression of MAPK is associated with the downregulation of TNF-alpha, IL-6, and IL-10 in Mycobacterium abscessus lung disease. Tuberc Respir Dis 72(3):275–283. doi:10.4046/trd.2012.72.3.275

    Article  Google Scholar 

  40. Flynn JL, Goldstein MM, Triebold KJ, Koller B, Bloom BR (1992) Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 89(24):12013–12017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cooper AM (2009) T cells in mycobacterial infection and disease. Curr Opin Immunol 21(4):378–384. doi:10.1016/j.coi.2009.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stephen-Victor E, Saha C, Sharma M, Holla S, Balaji KN, Kaveri SV, Bayry J (2015) Inhibition of programmed death 1 ligand 1 on dendritic cells enhances mycobacterium-mediated interferon gamma (IFN-gamma) production without modulating the frequencies of IFN-gamma-Producing CD4+ T cells. J Infect Dis 211(6):1027–1029. doi:10.1093/infdis/jiu532

    Article  PubMed  Google Scholar 

  43. Lalvani A, Brookes R, Wilkinson RJ, Malin AS, Pathan AA, Andersen P, Dockrell H, Pasvol G, Hill AV (1998) Human cytolytic and interferon gamma-secreting CD8+ T lymphocytes specific for Mycobacterium tuberculosis. Proc Natl Acad Sci USA 95(1):270–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Baliko Z, Szereday L, Szekeres-Bartho J (1998) Th2 biased immune response in cases with active Mycobacterium tuberculosis infection and tuberculin anergy. FEMS Immunol Med Microbiol 22(3):199–204

    Article  CAS  PubMed  Google Scholar 

  45. Doherty TM, Rook G (2006) Progress and hindrances in tuberculosis vaccine development. Lancet 367(9514):947–949. doi:10.1016/S0140-6736(06)68389-X

    Article  PubMed  Google Scholar 

  46. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35. doi:10.1038/nri978

    Article  CAS  PubMed  Google Scholar 

  47. Agger EM, Cassidy JP, Brady J, Korsholm KS, Vingsbo-Lundberg C, Andersen P (2008) Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection. Immunology 124(2):175–185. doi:10.1111/j.1365-2567.2007.02751.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim SY, Koh WJ, Kim YH, Jeong BH, Park HY, Jeon K, Kim JS, Cho SN, Shin SJ (2014) Importance of reciprocal balance of T cell immunity in Mycobacterium abscessus complex lung disease. PLoS ONE 9(10):e109941. doi:10.1371/journal.pone.0109941

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from Chinese National Key Project of Infectious Disease (2012ZX10003008-004) and The Fund of Doctoral Scientific Research of MOE (20110181110046).

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Authors and Affiliations

  1. Laboratory of Infection and Immunity, School of Basic Medical Sciences, Sichuan University, Chengdu, 610041, China

    Wei Chen, Xueli Gong, Dongqing Gu, Youjun Mi & Lang Bao

  2. Department of Urology, West China Hospital, Sichuan University, Chengdu, China

    Yige Bao

  3. Department of Respiratory Disease and Tuberculosis, West China Hospital, Sichuan University, Chengdu, China

    Xuerong Chen

  4. Division of Urology, Department of Surgery, The University of Western Ontario, London, Canada

    Jeremy Burton

  5. Department of Microbiology and Immunology, The University of Western Ontario, London, Canada

    Jeremy Burton

  6. Canadian Centre for Human Microbiome and Probiotics, Lawson Health Research Institute, London, Canada

    Jeremy Burton

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  1. Wei Chen
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Correspondence to Lang Bao.

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Chen, W., Bao, Y., Chen, X. et al. Mycobacterium tuberculosis PE25/PPE41 protein complex induces activation and maturation of dendritic cells and drives Th2-biased immune responses. Med Microbiol Immunol 205, 119–131 (2016). https://doi.org/10.1007/s00430-015-0434-x

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