DOI QR코드

DOI QR Code

Antimicrobial Peptides in Innate Immunity against Mycobacteria

  • Shin, Dong-Min (Department of Microbiology and Infection Signaling Network Research Center, Chungnam National University, School of Medicine) ;
  • Jo, Eun-Kyeong (Department of Microbiology and Infection Signaling Network Research Center, Chungnam National University, School of Medicine)
  • Received : 2011.09.05
  • Accepted : 2011.09.02
  • Published : 2011.10.31

Abstract

Antimicrobial peptides/proteins are ancient and naturally-occurring antibiotics in innate immune responses in a variety of organisms. Additionally, these peptides have been recognized as important signaling molecules in regulation of both innate and adaptive immunity. During mycobacterial infection, antimicrobial peptides including cathelicidin, defensin, and hepcidin have antimicrobial activities against mycobacteria, making them promising candidates for future drug development. Additionally, antimicrobial peptides act as immunomodulators in infectious and inflammatory conditions. Multiple crucial functions of cathelicidins in antimycobacterial immune defense have been characterized not only in terms of direct killing of mycobacteria but also as innate immune regulators, i.e., in secretion of cytokines and chemokines, and mediating autophagy activation. Defensin families are also important during mycobacterial infection and contribute to antimycobacterial defense and inhibition of mycobacterial growth both in vitro and in vivo. Hepcidin, although its role in mycobacterial infection has not yet been characterized, exerts antimycobacterial effects in activated macrophages. The present review focuses on recent efforts to elucidate the roles of host defense peptides in innate immunity to mycobacteria.

Keywords

References

  1. WHO: Global Tubercalosis Control 2010. Geneva: WHO; 2010. 7.
  2. Pieters J: Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3;399-407, 2008. https://doi.org/10.1016/j.chom.2008.05.006
  3. Flynn JL, Chan J: Tuberculosis: latency and reactivation. Infect Immun 69;4195-4201, 2001. https://doi.org/10.1128/IAI.69.7.4195-4201.2001
  4. Zaiou M: Multifunctional antimicrobial peptides: therapeutic targets in several human diseases. J Mol Med 85; 317-329, 2007. https://doi.org/10.1007/s00109-006-0143-4
  5. Liu PT, Modlin RL: Human macrophage host defense against Mycobacterium tuberculosis. Curr Opin Immunol 20;371-376, 2008. https://doi.org/10.1016/j.coi.2008.05.014
  6. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311; 1770-1773, 2006. https://doi.org/10.1126/science.1123933
  7. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW: Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181;7090-7099, 2008. https://doi.org/10.4049/jimmunol.181.10.7090
  8. Cole AM, Waring AJ: The role of defensins in lung biology and therapy. Am J Respir Med 1; 249-259, 2002. https://doi.org/10.1007/BF03256616
  9. Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M, Vazirnia A, Zhang X, Steinmeyer A, Zugel U, Hollis BW, Cheng G, Modlin RL: Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS One 4;e5-810, 2009.
  10. Sow FB, Florence WC, Satoskar AR, Schlesinger LS, Zwilling BS, Lafuse WP: Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol 82;934-945, 2007. https://doi.org/10.1189/jlb.0407216
  11. Beisswenger C, Bals R: Functions of antimicrobial peptides in host defense and immunity. Curr Protein Pept Sci 6; 255-264, 2005. https://doi.org/10.2174/1389203054065428
  12. Lehrer RI, Ganz T: Cathelicidins: a family of endogenous antimicrobial peptides. Curr Opin Hematol 9;18-22, 2002. https://doi.org/10.1097/00062752-200201000-00004
  13. Zanetti M: The role of cathelicidins in the innate host defenses of mammals. Curr Issues Mol Biol 7:179-196, 2005.
  14. Fahy RJ, Wewers MD: Pulmonary defense and the human cathelicidin hCAP-18/LL-37. Immunol Res 31;75-89, 2005. https://doi.org/10.1385/IR:31:2:075
  15. Zanetti M: Cathelicidins, multifunctional peptides of the innate immunity. J Leukoc Biol 75;39-48, 2004. https://doi.org/10.1189/jlb.0403147
  16. Lai Y, Gallo RL: AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol 30;131-141, 2009. https://doi.org/10.1016/j.it.2008.12.003
  17. Yuk JM, Shin DM, Lee HM, Yang CS, Jin HS, Kim KK, Lee ZW, Lee SH, Kim JM, Jo EK: Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6;231-243, 2009. https://doi.org/10.1016/j.chom.2009.08.004
  18. Lehrer RI, Lichtenstein AK, Ganz T: Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol 11;105-128, 1993. https://doi.org/10.1146/annurev.iy.11.040193.000541
  19. Driss V, Legrand F, Hermann E, Loiseau S, Guerardel Y, Kremer L, Adam E, Woerly G, Dombrowicz D, Capron M: TLR2-dependent eosinophil interactions with mycobacteria: role of alpha-defensins. Blood 113;3235-3244, 2009. https://doi.org/10.1182/blood-2008-07-166595
  20. Kisich KO, Heifets L, Higgins M, Diamond G: Antimycobacterial agent based on mRNA encoding human beta-defensin 2 enables primary macrophages to restrict growth of Mycobacterium tuberculosis. Infect Immun 69;2692-2699, 2001. https://doi.org/10.1128/IAI.69.4.2692-2699.2001
  21. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schroder JM, Wang JM, Howard OM, Oppenheim JJ: Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286;525-528, 1999. https://doi.org/10.1126/science.286.5439.525
  22. De Smet K, Contreras R: Human antimicrobial peptides: defensins, cathelicidins and histatins. Biotechnol Lett 27; 1337-1347, 2005. https://doi.org/10.1007/s10529-005-0936-5
  23. O'Neil DA, Porter EM, Elewaut D, Anderson GM, Eckmann L, Ganz T, Kagnoff MF: Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 163;6718-6724, 1999.
  24. Becker MN, Diamond G, Verghese MW, Randell SH: CD14- dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem 275;29731-29736, 2000. https://doi.org/10.1074/jbc.M000184200
  25. Oppenheim JJ, Biragyn A, Kwak LW, Yang D: Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann Rheum Dis 62(Suppl 2);ii17-21, 2003.
  26. Kai-Larsen Y, Agerberth B: The role of the multifunctional peptide LL-37 in host defense. Front Biosci 13;3760-3767, 2008.
  27. Rivas-Santiago B, Hernandez-Pando R, Carranza C, Juarez E, Contreras JL, Aguilar-Leon D, Torres M, Sada E: Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. Infect Immun 76;935-941, 2008. https://doi.org/10.1128/IAI.01218-07
  28. Martineau AR, Newton SM, Wilkinson KA, Kampmann B, Hall BM, Nawroly N, Packe GE, Davidson RN, Griffiths CJ, Wilkinson RJ: Neutrophil-mediated innate immune resistance to mycobacteria. J Clin Invest 117;1988-1994, 2007. https://doi.org/10.1172/JCI31097
  29. Bals R, Wang X, Zasloff M, Wilson JM: The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc Natl Acad Sci U S A 95;9541-9546, 1998. https://doi.org/10.1073/pnas.95.16.9541
  30. Agerberth B, Grunewald J, Castanos-Velez E, Olsson B, Jornvall H, Wigzell H, Eklund A, Gudmundsson GH: Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med 160;283-290, 1999. https://doi.org/10.1164/ajrccm.160.1.9807041
  31. Lee HM, Shin DM, Choi DK, Lee ZW, Kim KH, Yuk JM, Kim CD, Lee JH, Jo EK: Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes. Cell Microbiol 11;678-692, 2009. https://doi.org/10.1111/j.1462-5822.2009.01285.x
  32. Yang CS, Shin DM, Kim KH, Lee ZW, Lee CH, Park SG, Bae YS, Jo EK: NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. J Immunol 182;3696-3705, 2009. https://doi.org/10.4049/jimmunol.0802217
  33. Mendez-Samperio P, Perez A, Torres L: Role of reactive oxygen species (ROS) in Mycobacterium bovis bacillus Calmette Guérin-mediated up-regulation of the human cathelicidin LL-37 in A549 cells. Microb Pathog 47;252-257, 2009. https://doi.org/10.1016/j.micpath.2009.08.006
  34. Jo EK: Innate immunity to mycobacteria: vitamin D and autophagy. Cell Microbiol 12;1026-1035, 2010. https://doi.org/10.1111/j.1462-5822.2010.01491.x
  35. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V: Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119;753-766, 2004. https://doi.org/10.1016/j.cell.2004.11.038
  36. Shin DM, Yuk JM, Lee HM, Lee SH, Son JW, Harding CV, Kim JM, Modlin RL, Jo EK: Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling. Cell Microbiol 12;1648-1665, 2010. https://doi.org/10.1111/j.1462-5822.2010.01497.x
  37. De Yang, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, Oppenheim JJ, Chertov O: LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192;1069-1074, 2000. https://doi.org/10.1084/jem.192.7.1069
  38. Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D: Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 174;6257-6265, 2005. https://doi.org/10.4049/jimmunol.174.10.6257
  39. Edfeldt K, Liu PT, Chun R, Fabri M, Schenk M, Wheelwright M, Keegan C, Krutzik SR, Adams JS, Hewison M, Modlin RL: T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci U S A 107;22593-22598, 2010. https://doi.org/10.1073/pnas.1011624108
  40. Ganz T: Antimicrobial polypeptides in host defense of the respiratory tract. J Clin Invest 109;693-697, 2002. https://doi.org/10.1172/JCI0215218
  41. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez- Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC: Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286;113-117, 1999. https://doi.org/10.1126/science.286.5437.113
  42. Schutte BC, Mitros JP, Bartlett JA, Walters JD, Jia HP, Welsh MJ, Casavant TL, McCray PB Jr: Discovery of five conserved beta -defensin gene clusters using a computational search strategy. Proc Natl Acad Sci U S A 99;2129-2133, 2002. https://doi.org/10.1073/pnas.042692699
  43. Jacobsen M, Repsilber D, Gutschmidt A, Neher A, Feldmann K, Mollenkopf HJ, Ziegler A, Kaufmann SH: Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis. J Mol Med (Berl) 85;613-621, 2007. https://doi.org/10.1007/s00109-007-0157-6
  44. Kalita A, Verma I, Khuller GK: Role of human neutrophil peptide-1 as a possible adjunct to antituberculosis chemotherapy. J Infect Dis 190;1476-1480, 2004. https://doi.org/10.1086/424463
  45. Harder J, Meyer-Hoffert U, Teran LM, Schwichtenberg L, Bartels J, Maune S, Schröder JM: Mucoiod Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6, induce human beta-defensin-2 in respiratory epithelia. Am J Respir Cell Mol Biol 22;714-721, 2000. https://doi.org/10.1165/ajrcmb.22.6.4023
  46. Mendez-Samperio P, Miranda E, Trejo A: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) stimulates human beta- defensin-2 gene transcription in human epithelial cells. Cell Immunol 239;61-66, 2006 https://doi.org/10.1016/j.cellimm.2006.04.001
  47. Rivas-Santiago CE, Rivas-Santiago B, Leon DA, Castaneda- Delgado J, Hernadez Pando R: Induction of ${\beta}$-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. Clin Exp Immunol 164;80-89, 2011. https://doi.org/10.1111/j.1365-2249.2010.04313.x
  48. Aguilar Leon D, Zumárraga MJ, Jimenez Oropeza R, Gioffre AK, Bernardelli A, Orozco Estevez H, Cataldi AA, Hernández Pando R: Mycobacterium bovis with different genotypes and from different hosts induce dissimilar immunopathological lesions in a mouse model of tuberculosis. Clin Exp Immunol 157;139-147, 2009. https://doi.org/10.1111/j.1365-2249.2009.03923.x
  49. Rivas-Santiago B, Sada E, Tsutsumi V, Aguilar-Leon D, Contreras JL, Hernandez-Pando R: beta-Defensin gene expression during the course of experimental tuberculosis infection. J Infect Dis 194;697-701, 2006. https://doi.org/10.1086/506454
  50. Cole AM, Wang W, Waring AJ, Lehrer RI: Retrocyclins: using past as prologue. Curr Protein Pept Sci 5;373-381, 2004. https://doi.org/10.2174/1389203043379657
  51. Tang YQ, Yuan J, Osapay G, Osapay K, Tran D, Miller CJ, Ouellette AJ, Selsted ME: A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. Science 286;498-502, 1999. https://doi.org/10.1126/science.286.5439.498
  52. Leonova L, Kokryakov VN, Aleshina G, Hong T, Nguyen T, Zhao C, Waring AJ, Lehrer RI: Circular minidefensins and posttranslational generation of molecular diversity. J Leukoc Biol 70;461-464, 2001.
  53. Tran D, Tran PA, Tang YQ, Yuan J, Cole T, Selsted ME: Homodimeric theta-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides. J Biol Chem 277;3079-3084, 2002. https://doi.org/10.1074/jbc.M109117200
  54. Brandt CR, Akkarawongsa R, Altmann S, Jose G, Kolb AW, Waring AJ, Lehrer RI: Evaluation of a theta-defensin in a Murine model of herpes simplex virus type 1 keratitis. Invest Ophthalmol Vis Sci 48;5118-5124, 2007. https://doi.org/10.1167/iovs.07-0302
  55. Wang W, Cole AM, Hong T, Waring AJ, Lehrer RI: Retrocyclin, an antiretroviral theta-defensin, is a lectin. J Immunol 170;4708-4716, 2003. https://doi.org/10.4049/jimmunol.170.9.4708
  56. Yang C, Boone L, Nguyen TX, Rudolph D, Limpakarnjanarat K, Mastro TD, Tappero J, Cole AM, Lal RB: Theta-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand. Infect Genet Evol 5;11-15, 2005. https://doi.org/10.1016/j.meegid.2004.05.006
  57. Ganz T: Hepcidin and its role in regulating systemic iron metabolism. Hematology Am Soc Hematol Educ Program 29-35, 2006.
  58. Ganz T: Hepcidin--a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol 306;183-198, 2006.
  59. Ganz T, Nemeth E: Iron sequestration and anemia of inflammation. Semin Hematol 46;387-393, 2009. https://doi.org/10.1053/j.seminhematol.2009.06.001
  60. Nemeth E, Ganz T: The role of hepcidin in iron metabolism. Acta Haematol 122;78-86, 2009. https://doi.org/10.1159/000243791
  61. Atanasiu V, Manolescu B, Stoian I: Hepcidin the link between inflammation and anemia in chronic renal failure. Rom J Intern Med 44;25-33, 2006.
  62. Sow FB, Alvarez GR, Gross RP, Satoskar AR, Schlesinger LS, Zwilling BS, Lafuse WP: Role of STAT1, NF-kappaB, and C/EBPbeta in the macrophage transcriptional regulation of hepcidin by mycobacterial infection and IFNgamma. J Leukoc Biol 86;1247-258, 2009. https://doi.org/10.1189/jlb.1208719

Cited by

  1. Identification of Mycobacterium avium genes associated with resistance to host antimicrobial peptides vol.63, pp.7, 2011, https://doi.org/10.1099/jmm.0.072744-0
  2. NR1D1 ameliorates Mycobacterium tuberculosis clearance through regulation of autophagy vol.11, pp.11, 2015, https://doi.org/10.1080/15548627.2015.1091140
  3. Short, Synthetic Cationic Peptides Have Antibacterial Activity against Mycobacterium smegmatis by Forming Pores in Membrane and Synergizing with Antibiotics vol.4, pp.3, 2011, https://doi.org/10.3390/antibiotics4030358
  4. Host Antimicrobial Peptides: The Promise of New Treatment Strategies against Tuberculosis vol.8, pp.None, 2011, https://doi.org/10.3389/fimmu.2017.01499
  5. Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design vol.11, pp.None, 2011, https://doi.org/10.3389/fnins.2017.00073
  6. Modulation of iron status biomarkers in tuberculosis-diabetes co-morbidity vol.108, pp.None, 2018, https://doi.org/10.1016/j.tube.2017.11.011
  7. IL-12+IL-18 Cosignaling in Human Macrophages and Lung Epithelial Cells Activates Cathelicidin and Autophagy, Inhibiting Intracellular Mycobacterial Growth vol.200, pp.7, 2018, https://doi.org/10.4049/jimmunol.1701073
  8. Metabolomics applied to the discovery of tuberculosis and diabetes mellitus biomarkers vol.12, pp.9, 2011, https://doi.org/10.2217/bmm-2018-0050
  9. Calcitriol enhances pyrazinamide treatment of murine tuberculosis vol.132, pp.17, 2011, https://doi.org/10.1097/cm9.0000000000000394
  10. Mycobacterial infection induces eosinophilia and production of α-defensin by eosinophils in mice vol.81, pp.1, 2011, https://doi.org/10.1292/jvms.18-0619
  11. Potentials of Host-Directed Therapies in Tuberculosis Management vol.8, pp.8, 2011, https://doi.org/10.3390/jcm8081166
  12. Eukaryotic Expression and Purification of Mature Bovine Neutrophil β-Defensins 4 vol.9, pp.4, 2011, https://doi.org/10.12677/hjbm.2019.94025
  13. Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection vol.10, pp.8, 2011, https://doi.org/10.3390/app10082688
  14. Mycogenic Metal Nanoparticles for the Treatment of Mycobacterioses vol.9, pp.9, 2020, https://doi.org/10.3390/antibiotics9090569
  15. Super-Resolution Microscopy Reveals a Direct Interaction of Intracellular Mycobacterium tuberculosis with the Antimicrobial Peptide LL-37 vol.21, pp.18, 2011, https://doi.org/10.3390/ijms21186741
  16. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity vol.12, pp.11, 2020, https://doi.org/10.3390/nu12113361
  17. Genetic Involvement of Mycobacterium avium Complex in the Regulation and Manipulation of Innate Immune Functions of Host Cells vol.22, pp.6, 2021, https://doi.org/10.3390/ijms22063011
  18. Evaluation of antimicrobial photodynamic activities of 5‐aminolevulinic acid derivatives vol.37, pp.4, 2011, https://doi.org/10.1111/phpp.12652
  19. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases vol.34, pp.4, 2011, https://doi.org/10.1128/cmr.00064-21