Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Understanding the Roles of Host Defense Peptides in Immune Modulation: From Antimicrobial Action to Potential as Adjuvants

  • Ju Kim (Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Jeonbuk National University) ;
  • Byeol-Hee Cho (Innovative Research and Education Center for Integrated Bioactive Materials and the Department of Bioactive Material Science, Jeonbuk National University) ;
  • Yong-Suk Jang (Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Jeonbuk National University)
  • Received : 2023.01.03
  • Accepted : 2023.02.07
  • Published : 2023.03.28
Download PDF
⟨ Previous Next ⟩

Abstract

Host defense peptides are expressed in various immune cells, including phagocytic cells and epithelial cells. These peptides selectively alter innate immune pathways in response to infections by pathogens, such as bacteria, fungi, and viruses, and modify the subsequent adaptive immune environment. Consequently, they play a wide range of roles in both innate and adaptive immune responses. These peptides are of increasing importance due to their broad-spectrum antimicrobial activity and their functions as mediators linking innate and adaptive immune responses. This review focuses on the pleiotropic biological functions and related mechanisms of action of human host defense peptides and discusses their potential clinical applications.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Programs (2020K1A4A7A02095058 to Y.-S. Jang and 2019R1I1A3A01062224 to J. Kim) through the National Research Foundation (NRF) of Korea funded by the Ministry of Education. Dr. Yong-Suk Jang was supported by the Research Base Construction Fund Program funded by Jeonbuk National University in 2023. B.-H. Cho was supported by the BK21 FOUR program in the Department of Bioactive Material Sciences. Some experiments described in this manuscript were performed using the instruments installed in the Center for University-Wide Research Facilities (CURF) at Jeonbuk National University.

References

  1. Konno K, Rangel M, Oliveira JS, Dos Santos Cabrera MP, Fontana R, Hirata IY, et al. 2007. Decoralin, a novel linear cationic alpha-helical peptide from the venom of the solitary eumenine wasp Oreumenes decoratus. Peptides 28: 2320-2327. https://doi.org/10.1016/j.peptides.2007.09.017
  2. Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ. 2004. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu. Rev. Immunol. 22: 181-215. https://doi.org/10.1146/annurev.immunol.22.012703.104603
  3. Pisano E, Cabras T, Montaldo C, Piras V, Inzitari R, Olmi C, et al. 2005. Peptides of human gingival crevicular fluid determined by HPLC-ESI-MS. Eur. J. Oral. Sci. 113: 462-468. https://doi.org/10.1111/j.1600-0722.2005.00246.x
  4. Wang G, Li X, Wang Z. 2009. APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acids Res. 37: D933-937. https://doi.org/10.1093/nar/gkn823
  5. Wang G. 2015. Improved methods for classification, prediction, and design of antimicrobial peptides. Methods Mol. Biol. 1268: 43-66. https://doi.org/10.1007/978-1-4939-2285-7_3
  6. Poirel L, Al Maskari Z, Al Rashdi F, Bernabeu S, Nordmann P. 2011. NDM-1-producing Klebsiella pneumoniae isolated in the Sultanate of Oman. J. Antimicrob. Chemother. 66: 304-306. https://doi.org/10.1093/jac/dkq428
  7. Sansom M. 1998. Peptides and lipid bilayers: dynamic interactions. Curr. Opin. Colloid Interface Sci. 3: 518-524. https://doi.org/10.1016/S1359-0294(98)80027-7
  8. Brogden KA. 2005. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3: 238-250. https://doi.org/10.1038/nrmicro1098
  9. Yang L, Harroun TA, Weiss TM, Ding L, Huang HW. 2001. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys. J. 81: 1475-1485. https://doi.org/10.1016/S0006-3495(01)75802-X
  10. Yeaman MR, Yount NY. 2003. Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev. 55: 27-55. https://doi.org/10.1124/pr.55.1.2
  11. Madani F, Lindberg S, Langel U, Futaki S, Graslund A. 2011. Mechanisms of cellular uptake of cell-penetrating peptides. J. Biophys. 2011: 414729.
  12. Lehrer RI. 2004. Primate defensins. Nat. Rev. Microbiol. 2: 727-738. https://doi.org/10.1038/nrmicro976
  13. Currie SM, Findlay EG, McHugh BJ, Mackellar A, Man T, Macmillan D, et al. 2013. The human cathelicidin LL-37 has antiviral activity against respiratory syncytial virus. PLoS One 8: e73659.
  14. Beaumont PE, McHugh B, Gwyer Findlay E, Mackellar A, Mackenzie KJ, Gallo RL, et al. 2014. Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo. PLoS One 9: e99029.
  15. Mei HF, Jin XB, Zhu JY, Zeng AH, Wu Q, Lu XM, et al. 2012. Beta-defensin 2 as an adjuvant promotes anti-melanoma immune responses and inhibits the growth of implanted murine melanoma in vivo. PLoS One 7: e31328.
  16. Kohlgraf KG, Pingel LC, Dietrich DE, Brogden KA. 2010. Defensins as anti-inflammatory compounds and mucosal adjuvants. Fut. Microbiol. 5: 99-113. https://doi.org/10.2217/fmb.09.104
  17. Diamond G, Beckloff N, Weinberg A, Kisich KO. 2009. The roles of antimicrobial peptides in innate host defense. Curr. Pharm. Des. 15: 2377-2392. https://doi.org/10.2174/138161209788682325
  18. Greer A, Zenobia C, Darveau RP. 2013. Defensins and LL-37: a review of function in the gingival epithelium. Periodontol. 2000 63: 67-79. https://doi.org/10.1111/prd.12028
  19. Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW. 1989. Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family. J. Biol. Chem. 264: 11200-11203. https://doi.org/10.1016/S0021-9258(18)60449-1
  20. Gomes Pde S, Fernandes MH. 2010. Defensins in the oral cavity: distribution and biological role. J. Oral. Pathol. Med. 39: 1-9. https://doi.org/10.1111/j.1600-0714.2009.00832.x
  21. Fanali C, Inzitari R, Cabras T, Pisano E, Castagnola M, Celletti R, et al. 2008. Alpha-defensin levels in whole saliva of totally edentulous subjects. Int. J. Immunopathol. Pharmacol. 21: 845-849. https://doi.org/10.1177/039463200802100409
  22. Gorr SU. 2009. Antimicrobial peptides of the oral cavity. Periodontol. 2000 51: 152-180. https://doi.org/10.1111/j.1600-0757.2009.00310.x
  23. Gorr SU, Abdolhosseini M. 2011. Antimicrobial peptides and periodontal disease. J. Clin. Periodontol. 38 (Suppl 11): 126-141. https://doi.org/10.1111/j.1600-051X.2010.01664.x
  24. Allaker RP, Zihni C, Kapas S. 1999. An investigation into the antimicrobial effects of adrenomedullin on members of the skin, oral, respiratory tract and gut microflora. FEMS Immunol. Med. Microbiol. 23: 289-293. https://doi.org/10.1016/S0928-8244(98)00148-5
  25. Lehmann J, Retz M, Harder J, Krams M, Kellner U, Hartmann J, et al. 2002. Expression of human beta-defensins 1 and 2 in kidneys with chronic bacterial infection. BMC Infect. Dis. 2: 20.
  26. Li X, Duan D, Wang P, Han B, Xu Y. 2013. New finding of the expression of human beta defensin-4 in healthy gingiva. Hua Xi Kou Qiang Yi Xue Za Zhi 31: 165-168.
  27. Ouhara K, Komatsuzawa H, Yamada S, Shiba H, Fujiwara T, Ohara M, et al. 2005. Susceptibilities of periodontopathogenic and cariogenic bacteria to antibacterial peptides, beta-defensins and LL37, produced by human epithelial cells. J. Antimicrob. Chemother. 55: 888-896. https://doi.org/10.1093/jac/dki103
  28. Kosciuczuk EM, Lisowski P, Jarczak J, Strzalkowska N, Jozwik A, Horbanczuk J, et al. 2012. Cathelicidins: family of antimicrobial peptides. A review. Mol. Biol. Rep. 39: 10957-10970. https://doi.org/10.1007/s11033-012-1997-x
  29. Murakami M, Ohtake T, Dorschner RA, Gallo RL. 2002. Cathelicidin antimicrobial peptides are expressed in salivary glands and saliva. J. Dent. Res. 81: 845-850. https://doi.org/10.1177/154405910208101210
  30. Tecle T, Tripathi S, Hartshorn KL. 2010. Defensins and cathelicidins in lung immunity. Innate Immun. 16:151-159. https://doi.org/10.1177/1753425910365734
  31. Bergman P, Walter-Jallow L, Broliden K, Agerberth B, Soderlund J. 2007. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr. HIV Res. 5: 410-415. https://doi.org/10.2174/157016207781023947
  32. Barlow PG, Findlay EG, Currie SM, Davidson DJ. 2014. Antiviral potential of cathelicidins. Future Microbiol. 9: 55-73. https://doi.org/10.2217/fmb.13.135
  33. Yang D, Chen Q, Chertov O, Oppenheim JJ. 2000. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J. Leukoc. Biol. 68: 9-14. https://doi.org/10.1189/jlb.68.1.9
  34. Hancock RE, Sahl HG. 2006. Antimicrobial and host-defense peptides as new antiinfective therapeutic strategies. Nat. Biotechnol. 24: 1551-1557. https://doi.org/10.1038/nbt1267
  35. Aerts AM, Francois IE, Cammue BP, Thevissen K. 2008. The mode of antifungal action of plant, insect and human defensins. Cell. Mol. Life Sci. 65: 2069-2079. https://doi.org/10.1007/s00018-008-8035-0
  36. Klotman ME, Chang TL. 2006. Defensins in innate antiviral immunity. Nat. Rev. Immunol. 6: 447-456. https://doi.org/10.1038/nri1860
  37. Imamura M, Wada S, Ueda K, Saito A, Koizumi N, Iwahana H, et al. 2009. Multipeptide precursor structure of acaloleptin A isoforms, antibacterial peptides from the Udo longicorn beetle, Acalolepta luxuriosa. Dev. Comp. Immunol. 33: 1120-1127. https://doi.org/10.1016/j.dci.2009.06.004
  38. Yoe SM, Kang CS, Han SS, Bang IS. 2006. Characterization and cDNA cloning of hinnavin II, a cecropin family antibacterial peptide from the cabbage butterfly, Artogeia rapae. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 144: 199-205. https://doi.org/10.1016/j.cbpb.2006.02.010
  39. Giesemann T, Guttenberg G, Aktories K. 2008. Human alpha-defensins inhibit Clostridium difficile toxin B. Gastroenterology 134: 2049-2058. https://doi.org/10.1053/j.gastro.2008.03.008
  40. Schroder JM. 1999. Epithelial antimicrobial peptides: innate local host response elements. Cell. Mol. Life Sci. 56: 32-46. https://doi.org/10.1007/s000180050004
  41. Hoover DM, Wu Z, Tucker K, Lu W, Lubkowski J. 2003. Antimicrobial characterization of human beta-defensin 3 derivatives. Antimicrob. Agents Chemother. 47: 2804-2809. https://doi.org/10.1128/AAC.47.9.2804-2809.2003
  42. Wu Z, Hoover DM, Yang D, Boulegue C, Santamaria F, Oppenheim JJ, et al. 2003. Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 3. Proc. Natl. Acad. Sci. USA 100: 8880-8885. https://doi.org/10.1073/pnas.1533186100
  43. Maisetta G, Batoni G, Esin S, Florio W, Bottai D, Favilli F, et al. 2006. In vitro bactericidal activity of human beta-defensin 3 against multidrug-resistant nosocomial strains. Antimicrob. Agents Chemother. 50: 806-809. https://doi.org/10.1128/AAC.50.2.806-809.2006
  44. Zhu C, Tan H, Cheng T, Shen H, Shao J, Guo Y, et al. 2013. Human beta-defensin 3 inhibits antibiotic-resistant Staphylococcus biofilm formation. J. Surg. Res.183: 204-213. https://doi.org/10.1016/j.jss.2012.11.048
  45. Huang L, Ching CB, Jiang R, Leong SS. 2008. Production of bioactive human beta-defensin 5 and 6 in E. coli by soluble fusion expression. Protein Expression Purif. 61: 168-174. https://doi.org/10.1016/j.pep.2008.05.016
  46. Corrales-Garcia L, Ortiz E, Castaneda-Delgado J, Rivas-Santiago B, Corzo G. 2013. Bacterial expression and antibiotic activities of recombinant variants of human beta-defensins on pathogenic bacteria and M. tuberculosis. Protein Expression Purif. 89: 33-43.  https://doi.org/10.1016/j.pep.2013.02.007
  47. Kim JY. 2016. Human fungal pathogens: why should we learn? J. Microbiol. 54: 145-148. https://doi.org/10.1007/s12275-016-0647-8
  48. Revie NM, Iyer KR, Robbins N, Cowen LE. 2018. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45: 70-76. https://doi.org/10.1016/j.mib.2018.02.005
  49. Vriens K, Cammue BP, Thevissen K. 2014. Antifungal plant defensins: mechanisms of action and production. Molecules 19: 12280-12303. https://doi.org/10.3390/molecules190812280
  50. Parisi K, Shafee TMA, Quimbar P, van der Weerden NL, Bleackley MR, Anderson MA. 2019. The evolution, function and mechanisms of action for plant defensins. Semin. Cell Dev. Biol. 88: 107-118. https://doi.org/10.1016/j.semcdb.2018.02.004
  51. Puri S, Edgerton M. 2014. How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryot. Cell 13: 958-964. https://doi.org/10.1128/EC.00095-14
  52. Menzel LP, Chowdhury HM, Masso-Silva JA, Ruddick W, Falkovsky K, Vorona R, et al. 2017. Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism. Sci. Rep. 7: 4353.
  53. Baek JH, Lee SH. 2010. Isolation and molecular cloning of venom peptides from Orancistrocerus drewseni (Hymenoptera: Eumenidae). Toxicon 55: 711-718. https://doi.org/10.1016/j.toxicon.2009.10.023
  54. Dang XL, Tian JH, Yang WY, Wang WX, Ishibashi J, Asaoka A, et al. 2009. Bactrocerin-1: a novel inducible antimicrobial peptide from pupae of oriental fruit fly Bactrocera dorsalis Hendel. Arch. Insect. Biochem. Physiol. 71: 117-129. https://doi.org/10.1002/arch.20308
  55. Daher KA, Selsted ME, Lehrer RI. 1986. Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60: 1068-1074. https://doi.org/10.1128/jvi.60.3.1068-1074.1986
  56. Salvatore M, Garcia-Sastre A, Ruchala P, Lehrer RI, Chang T, Klotman ME. 2007. alpha-Defensin inhibits influenza virus replication by cell-mediated mechanism(s). J. Infect. Dis. 196: 835-843. https://doi.org/10.1086/521027
  57. Carballar-Lejarazu R, Rodriguez MH, de la Cruz Hernandez-Hernandez F, Ramos-Castaneda J, Possani LD, Zurita-Ortega M, et al. 2008. Recombinant scorpine: a multifunctional antimicrobial peptide with activity against different pathogens. Cell. Mol. Life Sci. 65: 3081-3092. https://doi.org/10.1007/s00018-008-8250-8
  58. Ryan LK, Diamond G, Amrute S, Feng Z, Weinberg A, Fitzgerald-Bocarsly P. 2003. Detection of HBD1 peptide in peripheral blood mononuclear cell subpopulations by intracellular flow cytometry. Peptides 24: 1785-1794. https://doi.org/10.1016/j.peptides.2003.09.021
  59. Ryan LK, Dai J, Yin Z, Megjugorac N, Uhlhorn V, Yim S, et al. 2011. Modulation of human beta-defensin-1 (hBD-1) in plasmacytoid dendritic cells (PDC), monocytes, and epithelial cells by influenza virus, Herpes simplex virus, and Sendai virus and its possible role in innate immunity. J. Leukoc. Biol. 90: 343-356. https://doi.org/10.1189/jlb.0209079
  60. Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV, et al. 2007. Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2. Proc. Natl. Acad. Sci. USA 104: 18631-18635. https://doi.org/10.1073/pnas.0702130104
  61. Cole AM, Hong T, Boo LM, Nguyen T, Zhao C, Bristol G, et al. 2002. Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. Proc. Natl. Acad. Sci. USA 99: 1813-1818. https://doi.org/10.1073/pnas.052706399
  62. Wilson SS, Wiens ME, Smith JG. 2013. Antiviral mechanisms of human defensins. J. Mol. Biol. 425: 4965-4980. https://doi.org/10.1016/j.jmb.2013.09.038
  63. Chertov O, Michiel DF, Xu L, Wang JM, Tani K, Murphy WJ, et al. 1996. Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J. Biol. Chem. 271: 2935-2940. https://doi.org/10.1074/jbc.271.6.2935
  64. Nagaoka I, Hirota S, Niyonsaba F, Hirata M, Adachi Y, Tamura H, et al. 2001. Cathelicidin family of antibacterial peptides CAP18 and CAP11 inhibit the expression of TNF-alpha by blocking the binding of LPS to CD14+ cells. J. Immunol. 167: 3329-3338. https://doi.org/10.4049/jimmunol.167.6.3329
  65. Rosenfeld Y, Papo N, Shai Y. 2006. Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J. Biol. Chem. 281: 1636-1643. https://doi.org/10.1074/jbc.M504327200
  66. Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, et al. 2006. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 176: 2455-2464. https://doi.org/10.4049/jimmunol.176.4.2455
  67. Merkle M, Pircher J, Mannell H, Krotz F, Blum P, Czermak T, et al. 2015. LL37 inhibits the inflammatory endothelial response induced by viral or endogenous DNA. J. Autoimmun. 65: 19-29. https://doi.org/10.1016/j.jaut.2015.07.015
  68. van Dijk A, van Eldik M, Veldhuizen EJ, Tjeerdsma-van Bokhoven HL, de Zoete MR, Bikker FJ, et al. 2016. Immunomodulatory and anti-inflammatory activities of chicken cathelicidin-2 derived peptides. PLoS One 11: e0147919.
  69. Mookherjee N, Wilson HL, Doria S, Popowych Y, Falsafi R, Yu JJ, et al. 2006. Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide. J. Leukoc. Biol. 80: 1563-1574. https://doi.org/10.1189/jlb.0106048
  70. Coorens M, Schneider VAF, de Groot AM, van Dijk A, Meijerink M, Wells JM, et al. 2017. Cathelicidins inhibit Escherichia coli-induced TLR2 and TLR4 activation in a viability-dependent manner. J. Immunol. 199: 1418-1428. https://doi.org/10.4049/jimmunol.1602164
  71. Choi KY, Napper S, Mookherjee N. 2014. Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation. Immunology 143: 68-80. https://doi.org/10.1111/imm.12291
  72. Li N, Yamasaki K, Saito R, Fukushi-Takahashi S, Shimada-Omori R, Asano M, et al. 2014. Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36gamma induction in human epidermal keratinocytes. J. Immunol. 193: 5140-5148. https://doi.org/10.4049/jimmunol.1302574
  73. Semple F, Webb S, Li HN, Patel HB, Perretti M, Jackson IJ, et al. 2010. Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo. Eur. J. Immunol. 40: 1073-1078. https://doi.org/10.1002/eji.200940041
  74. Semple F, MacPherson H, Webb S, Cox SL, Mallin LJ, Tyrrell C, et al. 2011. Human β-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF. Eur. J. Immunol. 41: 3291-3300. https://doi.org/10.1002/eji.201141648
  75. Funderburg NT, Jadlowsky JK, Lederman MM, Feng Z, Weinberg A, Sieg SF. 2011. The Toll-like receptor 1/2 agonists Pam3CSK4 and human beta-defensin-3 differentially induce interleukin-10 and nuclear factor-κB signalling patterns in human monocytes. Immunology 134: 151-160. https://doi.org/10.1111/j.1365-2567.2011.03475.x
  76. Severino P, Ariga SK, Barbeiro HV, de Lima TM, de Paula Silva E, Barbeiro DF, et al. 2017. Cathelicidin-deficient mice exhibit increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture. J. Mol. Med. 95: 995-1003. https://doi.org/10.1007/s00109-017-1555-z
  77. Wehkamp J, Schmid M, Fellermann K, Stange EF. 2005. Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn's disease. J. Leukoc. Biol. 77: 460-465.
  78. Wuerth KC, Falsafi R, Hancock REW. 2017. Synthetic host defense peptide IDR-1002 reduces inflammation in Pseudomonas aeruginosa lung infection. PLoS One 12: e0187565.
  79. Hou M, Zhang N, Yang J, Meng X, Yang R, Li J, et al. 2013. Antimicrobial peptide LL-37 and IDR-1 ameliorate MRSA pneumonia in vivo. Cell Physiol. Biochem. 32: 614-623. https://doi.org/10.1159/000354465
  80. Coorens M, Banaschewski BJH, Baer BJ, Yamashita C, van Dijk A, Haagsman HP, et al. 2017. Killing of P. aeruginosa by chicken cathelicidin-2 is immunogenically silent, preventing lung inflammation in vivo. Infect. Immun. 85: e00546-17.
  81. Chow LN, Choi KY, Piyadasa H, Bossert M, Uzonna J, Klonisch T, et al. 2014. Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis. Mol. Immunol. 57: 86-92. https://doi.org/10.1016/j.molimm.2013.08.011
  82. Tjabringa GS, Ninaber DK, Drijfhout JW, Rabe KF, Hiemstra PS. 2006. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int. Arch. Allergy Immunol. 140: 103-112. https://doi.org/10.1159/000092305
  83. Hemshekhar M, Choi KG, Mookherjee N. 2018. Host defense peptide LL-37-mediated chemoattractant properties, but not anti-inflammatory cytokine IL-1RA production, is selectively controlled by Cdc42 Rho GTPase via G protein-coupled receptors and JNK mitogen-activated protein kinase. Front. Immunol. 9: 1871.
  84. Hancock RE, Haney EF, Gill EE. 2016. The immunology of host defence peptides: beyond antimicrobial activity. Nat. Rev. Immunol. 16: 321-334.  https://doi.org/10.1038/nri.2016.29
  85. Nijnik A, Madera L, Ma S, Waldbrook M, Elliott MR, Easton DM, et al. 2010. Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J. Immunol. 184: 2539-2550. https://doi.org/10.4049/jimmunol.0901813
  86. Madera L, Hancock RE. 2012. Synthetic immunomodulatory peptide IDR-1002 enhances monocyte migration and adhesion on fibronectin. J. Innate Immun. 4: 553-568. https://doi.org/10.1159/000338648
  87. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. 2002. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J. Immunol. 169: 3883-3891. https://doi.org/10.4049/jimmunol.169.7.3883
  88. Choi KY, Mookherjee N. 2012. Multiple immunemodulatory functions of cathelicidin host defense peptides. Front. Immunol. 3: 149.
  89. Holly MK, Diaz K, Smith JG. 2017. Defensins in viral infection and pathogenesis. Annu. Rev. Virol. 4: 369-391. https://doi.org/10.1146/annurev-virology-101416-041734
  90. Agier J, Efenberger M, Brzezinska-Blaszczyk E. 2015. Cathelicidin impact on inflammatory cells. Cent. Eur. J. Immunol. 40: 225-235. https://doi.org/10.5114/ceji.2015.51359
  91. Suarez-Carmona M, Hubert P, Delvenne P, Herfs M. 2015. Defensins: "simple" antimicrobial peptides or broad-spectrum molecules? Cytokine Growth Factor Rev. 26: 361-370. https://doi.org/10.1016/j.cytogfr.2014.12.005
  92. Mookherjee N, Lippert DN, Hamill P, Falsafi R, Nijnik A, Kindrachuk J, et al. 2009. Intracellular receptor for human host defense peptide LL-37 in monocytes. J. Immunol. 183: 2688-2696. https://doi.org/10.4049/jimmunol.0802586
  93. Yu HB, Kielczewska A, Rozek A, Takenaka S, Li Y, Thorson L, et al. 2009. Sequestosome-1/p62 is the key intracellular target of innate defense regulator peptide. J. Biol. Chem. 284: 36007-36011. https://doi.org/10.1074/jbc.C109.073627
  94. Tewary P, de la Rosa G, Sharma N, Rodriguez LG, Tarasov SG, Howard OM, et al. 2013. Beta-defensin 2 and 3 promote the uptake of self or CpG DNA, enhance IFN-alpha production by human plasmacytoid dendritic cells, and promote inflammation. J. Immunol. 191: 865-874. https://doi.org/10.4049/jimmunol.1201648
  95. Kim J, Yang YL, Jang YS. 2019. Human β-defensin 2 is involved in CCR2-mediated Nod2 signal transduction, leading to activation of the innate immune response in macrophages. Immunobiology 224: 502-510. https://doi.org/10.1016/j.imbio.2019.05.004
  96. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, et al. 2002. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298: 1025-1029. https://doi.org/10.1126/science.1075565
  97. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, et al. 1999. Betadefensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286: 525-528. https://doi.org/10.1126/science.286.5439.525
  98. Kurosaka K, Chen Q, Yarovinsky F, Oppenheim JJ, Yang D. 2005. 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. https://doi.org/10.4049/jimmunol.174.10.6257
  99. Kim J, Yang YL, Jeong Y, Jang YS. 2020. Conjugation of human beta-defensin 2 to spike protein receptor-binding domain induces antigen-specific protective immunity against middle east respiratory syndrome coronavirus infection in human dipeptidyl peptidase 4 transgenic mice. Vaccines 8: 635.
  100. Maroti G, Kereszt A, Kondorosi E, Mergaert P. 2011. Natural roles of antimicrobial peptides in microbes, plants and animals. Res. Microbiol. 62: 363-374.
  101. Park CB, Yi KS, Matsuzaki K, Kim MS, Kim SC. 2000. Structure-activity analysis of buforin II, a histone H2A-derived antimicrobial peptide: the proline hinge is responsible for the cell-penetrating ability of buforin II. Proc. Natl. Acad. Sci. USA 97: 8245-8250. https://doi.org/10.1073/pnas.150518097
  102. Subbalakshmi C, Sitaram N. 1998. Mechanism of antimicrobial action of indolicidin. FEMS Microbiol. Lett. 160: 91-96. https://doi.org/10.1111/j.1574-6968.1998.tb12896.x
  103. Lai Y, Gallo RL. 2009. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 30: 131-141. https://doi.org/10.1016/j.it.2008.12.003
  104. Yeung ATY, Gellatly SL, Hancock REW. 2011. Multifunctional cationic host defence peptides and their clinical applications. Cell. Mol. Life Sci. 68: 2161-2176. https://doi.org/10.1007/s00018-011-0710-x
  105. Nicholls EF, Madera L, Hancock REW. 2010. Immunomodulators as adjuvants for vaccines and antimicrobial therapy. Ann. NY Acad. Sci. 1213: 46-61. https://doi.org/10.1111/j.1749-6632.2010.05787.x
  106. Brown KL, Poon GFT, Birkenhead D, Pena OM, Falsafi R, Dahlgren C, et al. 2011. Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. J. Immunol. 186: 5497-5505. https://doi.org/10.4049/jimmunol.1002508
  107. van der Does AM, Beekhuizen H, Ravensbergen B, Vos T, Ottenhoff THM, van Dissel JT, et al. 2010. LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature. J. Immunol. 185: 1442-1449. https://doi.org/10.4049/jimmunol.1000376
  108. An LL., Yang YH, Ma XT, Lin YM, Li G, Song YH, et al. 2005. LL-37 enhances adaptive antitumor immune response in a murine model when genetically fused with M-CSFR (J6-1) DNA vaccine. Leuk. Res. 29: 535-543. https://doi.org/10.1016/j.leukres.2004.11.009
  109. Davidson DJ, Currie AJ, Reid GSD, Bowdish DME, MacDonald KL, Ma RC, et al. 2004. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J. Immunol. 172: 1146-1156. https://doi.org/10.4049/jimmunol.172.2.1146
  110. van der Does AM, Hiemstra PS, Mookherjee N. 2019. Antimicrobial host defence peptides: immunomodulatory functions and translational prospects. Adv. Exp. Med. Biol. 1117: 149-171. https://doi.org/10.1007/978-981-13-3588-4_10
  111. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, et al. 2011. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 6: e25333.
  112. Sano H, Nagai K, Tsutsumi H, Kuroki Y. 2003. Lactoferrin and surfactant protein A exhibit distinct binding specificity to F protein and di_erently modulate respiratory syncytial virus infection. Eur. J. Immunol. 33: 2894-2902. https://doi.org/10.1002/eji.200324218
  113. Gronberg A, Mahlapuu M, Stahle M, Whately-Smith C, Rollman O. 2014. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 22: 613-621. https://doi.org/10.1111/wrr.12211
  114. Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N. 2003. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J. Immunol. 170: 5583-5589. https://doi.org/10.4049/jimmunol.170.11.5583
  115. Li D, Wang W, Shi HS, Fu YJ, Chen X, Chen XC, et al. 2014. Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects. Hum. Gene Ther. 25: 63-72. https://doi.org/10.1089/hum.2013.161
  116. Otvos, L. 2017. Host defense peptides and cancer; perspectives on research design and outcomes. Protein Pept. Lett. 24: 879-886. https://doi.org/10.2174/0929866524666170202153501
  117. Adams LG, Khare S, Lawhon SD, Rossetti CA, Lewin HA, Lipton MS, et al. 2011. Enhancing the role of veterinary vaccines reducing zoonotic diseases of humans: linking systems biology with vaccine development. Vaccine 29: 7197-206. https://doi.org/10.1016/j.vaccine.2011.05.080
  118. Rivas-Santiago B, Cervantes-Villagrana A, Sada E, Hernandez-Pando R. 2012. Expression of beta defensin 2 in experimental pulmonary tuberculosis: tentative approach for vaccine development. Arch. Med. Res. 43: 324-328. https://doi.org/10.1016/j.arcmed.2012.06.005
  119. Rohrl J, Yang D, Oppenheim JJ, Hehlgans T. 2010. Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. J. Immunol. 184: 6688-6694. https://doi.org/10.4049/jimmunol.0903984
  120. Ju SM, Goh AR, Kwon DJ, Youn GS, Kwon HJ, Bae YS, et al. 2012. Extracellular HIV-1 Tat induces human beta-defensin-2 production via NF-kappaB/AP-1 dependent pathways in human B cells. Mol. Cells 33: 335-341. https://doi.org/10.1007/s10059-012-2287-0
  121. Allaker RP. 2008. Host defence peptides-a bridge between the innate and adaptive immune responses. Trans. R. Soc. Trop. Med. Hyg. 102: 3-4. https://doi.org/10.1016/j.trstmh.2007.07.005
  122. Nierkens S, Tel J, Janssen E, Adema GJ. 2013. Antigen cross-presentation by dendritic cell subsets: one general or all sergeants? Trends. Immunol. 34: 361-370. https://doi.org/10.1016/j.it.2013.02.007
  123. Alu A, Chen L, Lei H, Wei Y, Tian X, Wei X. 2022. Intranasal COVID-19 vaccines: from bench to bed. EBioMedicine 76: 103841. 
  124. Kim J, Yang YL, Jeong Y, Jang YS. 2022. Application of antimicrobial peptide LL-37 as an adjuvant for middle east respiratory syndrome-coronavirus antigen induces an efficient protective immune response against viral infection after intranasal immunization. Immun. Netw. 22: e41.
  125. Coorens M, van Dijk A, Bikker F, Veldhuizen EJ, Haagsman HP. 2015. Importance of endosomal cathelicidin degradation to enhance DNA-induced chicken macrophage activation. J. Immunol. 195: 3970-3977. https://doi.org/10.4049/jimmunol.1501242
  126. Sandgren S, Wittrup A, Cheng F, Jonsson M, Eklund E, Busch S, et al. 2004. The human antimicrobial peptide LL-37 transfers extracellular DNA plasmid to the nuclear compartment of mammalian cells via lipid rafts and proteoglycan-dependent endocytosis. J. Biol. Chem. 279: 17951-17956. https://doi.org/10.1074/jbc.M311440200
  127. Jadhav NJ, Patil PS, Alagarasu K. 2019. Effect of full-length and truncated variants of LL-37 on dengue virus infection and immunomodulatory effects of LL-37 in dengue virus infected U937-DC-SIGN cells. Int. J. Pept. Res. Ther. 26: 547-555. https://doi.org/10.1007/s10989-019-09861-z
  128. Matsumura T, Sugiyama N, Murayama A, Yamada N, Shiina M, Asabe S, et al. 2016. Antimicrobial peptide LL-37 attenuates infection of hepatitis C virus. Hepatol. Res. 46: 924-932. https://doi.org/10.1111/hepr.12627
  129. Honda JR, Connick E, MaWhinney S, Chan ED, Flores SC. 2014. Plasma LL-37 correlates with vitamin D and is reduced in human immunodeficiency virus-1 infected individuals not receiving antiretroviral therapy. J. Med. Microbiol. 63: 997-1003. https://doi.org/10.1099/jmm.0.070888-0
  130. Schogler A, Muster RJ, Kieninger E, Casaulta C, Tapparel C, Jung A, et al. 2016. Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. Eur. Respir. J. 47: 520-530. https://doi.org/10.1183/13993003.00665-2015
  131. Lee CJ, Buznyk O, Kuffova, L, Rajendran V, Forrester JV, Phopase J, et al. 2014. Cathelicidin LL-37 and HSV-1 corneal infection: peptide versus gene therapy. Transl. Vis. Sci. Technol. 3: 4.
  132. Tripathi S, Verma A, Kim EJ, White MR, Hartshorn KL. 2014. LL-37 modulates human neutrophil responses to influenza A virus.J. Leukoc. Biol. 96: 931-938. https://doi.org/10.1189/jlb.4A1113-604RR
  133. Harcourt JL, McDonald M, Svoboda P, Pohl J, Tatti K, Haynes LM. 2016. Human cathelicidin, LL-37, inhibits respiratory syncytial virus infection in polarized airway epithelial cells. BMC Res. Notes 9: 11.
  134. Dean RE, O'Brien LM, Thwaite JE, Fox MA, Atkins H, Ulaeto DO. 2010. A carpet-based mechanism for direct antimicrobial peptide activity against vaccinia virus membranes. Peptides 31: 1966-1972. https://doi.org/10.1016/j.peptides.2010.07.028
  135. Ahmed A, Siman-Tov G, Keck F, Kortchak S, Bakovic A, Risner K, et al. 2019. Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections. Antiviral Res. 164: 61-69. https://doi.org/10.1016/j.antiviral.2019.02.002
  136. He M, Zhang H, Li Y, Wang G, Tang B, Zhao J, et al. 2018. Cathelicidin-derived antimicrobial peptides inhibit Zika virus through direct inactivation and interferon pathway. Front. Immunol. 9: 722.
  137. Chang TL, Vargas J Jr. DelPortillo A, Klotman ME. 2005. Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. J. Clin. Investig. 115: 765-773. https://doi.org/10.1172/JCI21948
  138. Smith JG, Nemerow GR. 2008. Mechanism of adenovirus neutralization by Human alpha-defensins. Cell Host Microbe 3: 11-19. https://doi.org/10.1016/j.chom.2007.12.001
  139. Hazrati E, Galen B, Lu W, Wang W, Ouyang Y, Keller MJ, et al. 2006. Human alphaand beta-defensins block multiple steps in herpes simplex virus infection. J. Immunol. 177: 8658-8666. https://doi.org/10.4049/jimmunol.177.12.8658
  140. Hsieh IN, Hartshorn KL. 2016. The role of antimicrobial peptides in influenza virus infection and their potential as antiviral and immunomodulatory therapy. Pharmaceuticals 9: 53.
  141. Buck CB, Day PM, Thompson CD, Lubkowski J, Lu W, Lowy DR, et al. 2006. Human alpha-defensins block papillomavirus infection. Proc. Natl. Acad. Sci. USA 103: 1516-1521. https://doi.org/10.1073/pnas.0508033103
  142. Wu Z, Cocchi F, Gentles D, Ericksen B, Lubkowski J, Devico A, et al. 2005. Human neutrophil alpha-defensin 4 inhibits HIV-1 infection in vitro. FEBS Lett. 579: 162-166. https://doi.org/10.1016/j.febslet.2004.11.062
  143. Furci L, Tolazzi M, Sironi F, Vassena L, Lusso P. 2012. Inhibition of HIV-1 infection by human alpha-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae. PLoS One 7: e45208.
  144. Wiens ME, Smith JG. 2017. Alpha-defensin HD5 inhibits human papillomavirus 16 infection via capsid stabilization and redirection to the lysosome. mBio 8: e02304.
  145. Galvan Morales MA, Escobar Gutierrez A, Rosete Olvera1 DP, Cabello Gutierrez C. 2015. Effect of human beta defensin-2 in epithelial cell lines infected with respiratory viruses. J. Bioanal. Biomed. 7: 136-143 https://doi.org/10.4172/1948-593X.1000135
  146. Quinones-Mateu ME, Lederman MM, Feng Z, Chakraborty B, Weber J, Rangel HR, et al. 2003. Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication. AIDS 17: F39-48. https://doi.org/10.1097/00002030-200311070-00001
  147. Kota S, Sabbah A, Chang TH, Harnack R, Xiang Y, Meng X, et al. 2008. Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus. J. Biol. Chem. 283: 22417-22429. https://doi.org/10.1074/jbc.M710415200
  148. Arnason JW, Murphy JC, Kooi C, Wiehler S, Traves SL, Shelfoon C, et al. 2017. Human β-defensin-2 production upon viral and bacterial co-infection is attenuated in COPD. PLoS One 12: e0175963.
  149. Howell MD, Streib JE, Leung DY. 2007. Antiviral activity of human beta-defensin 3 against vaccinia virus. J. Allergy Clin. Immunol. 119: 1022-1025. https://doi.org/10.1016/j.jaci.2007.01.044