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Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis

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Abstract

Mycobacterium tuberculosis PE/PPE family proteins, named after the presence of conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains at N-terminal, are prevalent in M. tuberculosis genome. The function of most PE/PPE family proteins remains elusive. To characterize the function of PE_PGRS18, the encoding gene was heterologously expressed in M. smegmatis, a nonpathogenic mycobacterium. The recombinant PE_PGRS18 is cell wall associated. M. smegmatis PE_PGRS18 recombinant showed differential response to stresses and altered the production of host cytokines IL-6, IL-1β, IL-12p40 and IL-10, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages. In summary, the study firstly unveiled the role of PE_PGRS18 in physiology and pathogenesis of mycobacterium.

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References

  1. Lin PL, Flynn JL (2010) Understanding latent tuberculosis: a moving target. J Immunol 185(1):15–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abdallah AM, Verboom T, Weerdenburg EM et al (2009) PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5. Mol Microbiol 73(3):329–340

    Article  CAS  PubMed  Google Scholar 

  3. Delogu G, Pusceddu C, Bua A et al (2004) Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Mol Microbiol 52(3):725–733

    Article  CAS  PubMed  Google Scholar 

  4. Bachhawat N, Singh B (2007) Mycobacterial PE PGRS proteins contain calcium-binding motifs with parallel β-roll folds. Genom Proteom Bioinform 5(3–4):236–241

    Article  CAS  Google Scholar 

  5. Talarico S, Zhang L, Marrs CF et al (2008) Mycobacterium tuberculosis PE_PGRS16 and PE_PGRS26 genetic polymorphism among clinical isolates. Tuberculosis (Edinb) 88(4):283–294

    Article  CAS  Google Scholar 

  6. Dheenadhayalan V, Delogu G, Sanguinetti M et al (2006) Variable expression patterns of Mycobacterium tuberculosis PE_PGRS genes: evidence that PE_PGRS16 and PE_PGRS26 are inversely regulated in vivo. J Bacteriol 188(10):3721–3725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Banu S, Honoré N, Saint-Joanis B et al (2002) Are the PE-PGRS proteins of Mycobacterium tuberculosis variable surface antigens? Mol Microbiol 44(1):9–19

    Article  CAS  PubMed  Google Scholar 

  8. Singh VK, Berry L, Bernut A et al (2016) A unique PE_PGRS protein inhibiting host cell cytosolic defenses and sustaining full virulence of Mycobacterium marinum in multiple hosts. Cell Microbiol 18(11):1489–1507

    Article  CAS  PubMed  Google Scholar 

  9. Ramakrishnan L, Federspiel NA, Falkow S (2000) Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288(5470):1436–1439

    Article  CAS  PubMed  Google Scholar 

  10. Srivastava V, Jain A, Srivastava BS et al (2008) Selection of genes of Mycobacterium tuberculosis upregulated during residence in lungs of infected mice. Tuberculosis 88(3):171–177

    Article  CAS  PubMed  Google Scholar 

  11. Meena, LS (2014) An overview to understand the role of PE_PGRS family proteins in Mycobacterium tuberculosis H 37 Rv and their potential as new drug targets. Biotechnol Appl BioChem 62(2):145–153

    Article  PubMed  Google Scholar 

  12. Lakshminarayan H, Narayanan S, Bach H et al (2008) Molecular cloning and biochemical characterization of a serine threonine protein kinase, PknL, from Mycobacterium tuberculosis. Protein Expr Purif 58(2):309–317

    Article  CAS  PubMed  Google Scholar 

  13. Deng W, Li W, Zeng J et al (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

    Article  CAS  PubMed  Google Scholar 

  14. Mazandu GK, Mulder NJ (2012) Function prediction and analysis of Mycobacterium tuberculosis hypothetical proteins. Int J Mol Sci 13(6):7283–7302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bottai D, Di Luca M, Majlessi L et al (2012) Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation. Mol Microbiol 83(6):1195–1209

    Article  CAS  PubMed  Google Scholar 

  16. Tiwari BM, Kannan N, Vemu L et al (2012) The Mycobacterium tuberculosis PE proteins Rv0285 and Rv1386 modulate innate immunity and mediate bacillary survival in macrophages. Plos ONE 7(12):e51686–e51686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Singh SK, Tripathi DK, Singh PK et al (2012) Protective and survival efficacies of Rv0160c protein in murine model of Mycobacterium tuberculosis. Appl Microbiol Biotechnol 97(13):5825–5837

    Article  PubMed  Google Scholar 

  18. Gupta D, Sharma S, Singhal J et al (2010) Suppression of TLR2-induced IL-12, reactive oxygen species, and inducible nitric oxide synthase expression by Mycobacterium tuberculosis antigens expressed inside macrophages during the course of infection. J Immunol 184(10):5444–5455

    Article  CAS  PubMed  Google Scholar 

  19. Voskuil MI, Schnappinger D, Visconti KC et al (2003) Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 198(5):705–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fishbein S, Wyk N, Warren RM et al (2015) Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity. Mol Microbiol 96(5):901–916

    Article  CAS  PubMed  Google Scholar 

  21. Leemans JC, Thepen T, Weijer S et al (2005) Macrophages play a dual role during pulmonary tuberculosis in mice. J Infect Dis 191(1):65–74

    Article  PubMed  Google Scholar 

  22. Flynn JL, Chan J (2003) Immune evasion by Mycobacterium tuberculosis: living with the enemy. Curr Opin Immunol 15(4):450–455

    Article  CAS  PubMed  Google Scholar 

  23. Delogu G, Brennan MJ (2001) Comparative immune response to PE and PE_PGRS antigens of Mycobacterium tuberculosis. Infect Immun 69(9):5606–5611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dheenadhayalan V, Delogu G, Brennan MJ (2006) Expression of the PE_PGRS 33 protein in Mycobacterium smegmatis triggers necrosis in macrophages and enhanced mycobacterial survival. Microbes Infect 8(1):262–272

    Article  CAS  PubMed  Google Scholar 

  25. Cadieux N, Parra M, Cohen H et al (2011) Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein. Microbiology 157(Pt 3):793–804

    Article  CAS  PubMed  Google Scholar 

  26. Chaitra MG, Shaila MS, Nayak R (2007) Evaluation of T-cell responses to peptides with MHC class I-binding motifs derived from PE_PGRS 33 protein of Mycobacterium tuberculosis. J Med Microbiol 56(Pt 4):466–474

    Article  CAS  PubMed  Google Scholar 

  27. Singh PP, Parra M, Cadieux N et al (2008) A comparative study of host response to three Mycobacterium tuberculosis PE_PGRS proteins. Microbiology 154(Pt 11):3469–3479

    Article  CAS  PubMed  Google Scholar 

  28. Chatrath S, Gupta VK, Dixit A et al (2016) PE_PGRS30 of Mycobacterium tuberculosis mediates suppression of proinflammatory immune response in macrophages through its PGRS and PE domains. Microbes Infect 18(9):536–542

    Article  CAS  PubMed  Google Scholar 

  29. Basu S, Pathak SK, Banerjee A et al (2007) Execution of macrophage apoptosis by PE_PGRS33 of Mycobacterium tuberculosis is mediated by Toll-like receptor 2-dependent release of tumor necrosis factor-alpha. J Biol Chem 282(2):1039–1050

    Article  CAS  PubMed  Google Scholar 

  30. Campuzano J, Aguilar D, Arriaga K et al (2007) The PGRS domain of Mycobacterium tuberculosis PE_PGRS Rv1759c antigen is an efficient subunit vaccine to prevent reactivation in a murine model of chronic tuberculosis. Vaccine 25(18):3722–3729

    Article  CAS  PubMed  Google Scholar 

  31. Jang S, Uematsu S, Akira S et al (2004) IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J Immunol 173(5):3392–3397

    Article  CAS  PubMed  Google Scholar 

  32. Fremond CM, Togbe D, Doz E et al (2007) IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J Immunol 179(2):1178–1189

    Article  CAS  PubMed  Google Scholar 

  33. Bordón J, Plankey MW, Young M et al (2011) Lower levels of interleukin-12 precede the development of tuberculosis among HIV-infected women. Cytokine 56(2):325–331

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cooper AM, Mayer-Barber KD, Sher A et al (2011) Role of innate cytokines in mycobacterial infection. Mucosal Immunol 4(3):252–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang Y, Wang Y, Bai Y et al (2010) Expression of PE_PGRS 62 protein in Mycobacterium smegmatis decrease mRNA expression of proinflammatory cytokines IL-1beta, IL-6 in macrophages. Mol Cell Biochem 340(1–2):223–229

    Article  CAS  PubMed  Google Scholar 

  36. Li J, Chai QY, Zhang Y et al (2015) Mycobacterium tuberculosis Mce3E suppresses host innate immune responses by targeting ERK1/2 signaling. J Immunol 194(8):3756–3767

    Article  CAS  PubMed  Google Scholar 

  37. Muttucumaru DGN, Smith DA, McMinn EJ et al (2011) Mycobacterium tuberculosis Rv0198c, a putative matrix metalloprotease is involved in pathogenicity. Tuberculosis (Edinb) 91(2):111–116

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation (Grant Nos. 81371851, 81071316, 81271882, 81301394), National Key Research and Development Program (2016YFC0502304), New Century Excellent Talents in Universities (Grant No. NCET-11-0703), The Fundamental Research Funds for the Central Universities (Grant No. XDJK2016E093), The Chongqing Municipal Committee of Education for postgraduates innovation program (Grant No. CYS16073). The Fundamental Research Funds for the Central Universities (Grant Nos. XDJK2016E093, XDJK2016D055, XDJK2012D007), The Chongqing Municipal Committee of Education for postgraduates innovation program (Grant No. CYS16073).

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    Authors and Affiliations

    1. State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Institute of Modern Biopharmaceuticals, Southwest University, Chongqing, China

      Wenmin Yang, Sai Ren, Md Kaisar Ali, Yinzhong Gu, Yangyuling Li & Jianping Xie

    2. Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

      Wanyan Deng

    3. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Schoolof Public Health, Xiamen University, Xiang-An, Xiamen, Fujian, China

      Jie Zeng

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    1. Wenmin Yang
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    Correspondence to Jianping Xie.

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    Wenmin Yang and Wanyan Deng have contributed equally to this work.

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    Yang, W., Deng, W., Zeng, J. et al. Mycobacterium tuberculosis PE_PGRS18 enhances the intracellular survival of M. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis. Apoptosis 22, 502–509 (2017). https://doi.org/10.1007/s10495-016-1336-0

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