Antimicrobial host defence peptides: functions and clinical potential

Abstract

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host’s immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Structures of CHDP.
Fig. 2: Models of antibacterial mechanisms of CHDP.
Fig. 3: Summary of immunomodulatory mechanisms of CHDP.
Fig. 4: Common resistance mechanisms to CHDP in bacterial and fungal pathogens.

References

  1. 1.

    Iannella, H., Luna, C. & Waterer, G. Inhaled corticosteroids and the increased risk of pneumonia: what’s new? A 2015 updated review. Ther. Adv. Respir. Dis. 10, 235–255 (2016).

  2. 2.

    Widdifield, J. et al. Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. Arthritis Care Res. 65, 353–361 (2013).

  3. 3.

    Clancy, C. J. et al. Emerging and resistant infections. Ann. Am. Thorac. Soc. 11, S193–S200 (2014).

  4. 4.

    Simmaco, M., Kreil, G. & Barra, D. Bombinins, antimicrobial peptides from Bombina species. Biochim. Biophys. Acta 1788, 1551–1555 (2009).

  5. 5.

    Steiner, H., Hultmark, D., Engstrom, A., Bennich, H. & Boman, H. G. Sequence and specificity of two antibacterial proteins involved in insect immunity. Nature 292, 246–248 (1981).

  6. 6.

    Ganz, T. et al. Defensins. Natural peptide antibiotics of human neutrophils. J. Clin. Invest. 76, 1427–1435 (1985).

  7. 7.

    Zasloff, M. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc. Natl Acad. Sci. USA 84, 5449–5453 (1987).

  8. 8.

    Bucki, R., Byfield, F. J. & Janmey, P. A. Release of the antimicrobial peptide LL-37 from DNA/F-actin bundles in cystic fibrosis sputum. Eur. Respir. J. 29, 624–632 (2007).

  9. 9.

    Bergsson, G. et al. LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline. J. Immunol. 183, 543–551 (2009).

  10. 10.

    Scott, M. G., Davidson, D. J., Gold, M. R., Bowdish, D. & Hancock, R. E. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J. Immunol. 169, 3883–3891 (2002). One of the first studies to demonstrate the immunomodulatory properties of CHDP LL-37 and discuss immunomodulation as being critical to the antimicrobial functions of the peptide.

  11. 11.

    Bowdish, D. M., Davidson, D. J., Scott, M. G. & Hancock, R. E. Immunomodulatory activities of small host defense peptides. Antimicrob. Agents Chemother. 49, 1727–1732 (2005).

  12. 12.

    Hancock, R. E., Haney, E. F. & Gill, E. E. The immunology of host defence peptides: beyond antimicrobial activity. Nat. Rev. Immunol. 16, 321–334 (2016).

  13. 13.

    Pantic, J. M. et al. The potential of frog skin-derived peptides for development into therapeutically-valuable immunomodulatory agents. Molecules 22, 2071 (2017).

  14. 14.

    Hemshekhar, M., Anaparti, V. & Mookherjee, N. Functions of cationic host defense peptides in immunity. Pharmaceuticals 9, 40 (2016).

  15. 15.

    van der Does, A. M., Hiemstra, P. S. & Mookherjee, N. Antimicrobial host defence peptides: immunomodulatory functions and translational prospects. Adv. Exp. Med. Biol. 1117, 149–171 (2019).

  16. 16.

    Mant, C. T. et al. De novo designed amphipathic alpha-helical antimicrobial peptides incorporating Dab and Dap residues on the polar face to treat the gram-negative pathogen, Acinetobacter baumannii. J. Med. Chem. 62, 3354–3366 (2019).

  17. 17.

    Jiang, S., Deslouches, B., Chen, C., Di, M. E. & Di, Y. P. Antibacterial properties and efficacy of a novel SPLUNC1-derived antimicrobial peptide, alpha4-short, in a murine model of respiratory infection. mBio 10, e00226-19 (2019).

  18. 18.

    Mishra, B., Reiling, S., Zarena, D. & Wang, G. Host defense antimicrobial peptides as antibiotics: design and application strategies. Curr. Opin. Chem. Biol. 38, 87–96 (2017).

  19. 19.

    Mai, S. et al. Potential applications of antimicrobial peptides and their mimics in combating caries and pulpal infections. Acta Biomater. 49, 16–35 (2017).

  20. 20.

    Chow, L. N. et al. Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis. Mol. Immunol. 57, 86–92 (2013).

  21. 21.

    Piyadasa, H. et al. Immunomodulatory innate defence regulator (IDR) peptide alleviates airway inflammation and hyper-responsiveness. Thorax 73, 908–917 (2018). The first study to demonstrate the therapeutic potential of an IDR peptide in allergen-challenged airway inflammation in the context of asthma.

  22. 22.

    Ho, S., Pothoulakis, C. & Koon, H. W. Antimicrobial peptides and colitis. Curr. Pharm. Des. 19, 40–47 (2013).

  23. 23.

    Li, D. et al. Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects. Hum. Gene Ther. 25, 63–72 (2014).

  24. 24.

    Scott, R. W. & Tew, G. N. Mimics of host defense proteins; strategies for translation to therapeutic applications. Curr. Top. Med. Chem. 17, 576–589 (2017).

  25. 25.

    Wang, G., Li, X. & Wang, Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 44, D1087–D1093 (2016).

  26. 26.

    Murakami, M., Lopez-Garcia, B., Braff, M., Dorschner, R. A. & Gallo, R. L. Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J. Immunol. 172, 3070–3077 (2004).

  27. 27.

    Sochacki, K. A., Barns, K. J., Bucki, R. & Weisshaar, J. C. Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL-37. Proc. Natl Acad. Sci. USA 108, E77–E81 (2011). The real-time attack on E. coli by the cathelicidin LL-37 is visualized for the first time.

  28. 28.

    Schneider, V. A. et al. Imaging the antimicrobial mechanism(s) of cathelicidin-2. Sci. Rep. 6, 32948 (2016).

  29. 29.

    van Harten, R. M., van Woudenbergh, E., van Dijk, A. & Haagsman, H. P. Cathelicidins: immunomodulatory antimicrobials. Vaccines 6, 63 (2018).

  30. 30.

    Mookherjee, N., Rehaume, L. M. & Hancock, R. E. Cathelicidins and functional analogues as antisepsis molecules. Expert. Opin. Ther. Targets 11, 993–1004 (2007).

  31. 31.

    Zanetti, M. Cathelicidins, multifunctional peptides of the innate immunity. J. Leukoc. Biol. 75, 39–48 (2004).

  32. 32.

    Patil, A., Hughes, A. L. & Zhang, G. Rapid evolution and diversification of mammalian alpha-defensins as revealed by comparative analysis of rodent and primate genes. Physiol. Genomics 20, 1–11 (2004).

  33. 33.

    Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).

  34. 34.

    Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).

  35. 35.

    Semple, F. & Dorin, J. R. β-Defensins: multifunctional modulators of infection, inflammation and more? J. Innate Immun. 4, 337–348 (2012).

  36. 36.

    Bevins, C. L., Jones, D. E., Dutra, A., Schaffzin, J. & Muenke, M. Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships. Genomics 31, 95–106 (1996).

  37. 37.

    Semple, C. A., Rolfe, M. & Dorin, J. R. Duplication and selection in the evolution of primate beta-defensin genes. Genome Biol. 4, R31 (2003).

  38. 38.

    Morrison, G. M., Semple, C. A., Kilanowski, F. M., Hill, R. E. & Dorin, J. R. Signal sequence conservation and mature peptide divergence within subgroups of the murine beta-defensin gene family. Mol. Biol. Evol. 20, 460–470 (2003).

  39. 39.

    Gudmundsson, G. H. et al. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur. J. Biochem. 238, 325–332 (1996). A seminal study which defines post-translational processing of cathelin precursor propeptide to the mature CHDP LL-37.

  40. 40.

    van Dijk, A. et al. Chicken heterophils are recruited to the site of Salmonella infection and release antibacterial mature cathelicidin-2 upon stimulation with LPS. Mol. Immunol. 46, 1517–1526 (2009).

  41. 41.

    Gallo, R. L. et al. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J. Biol. Chem. 272, 13088–13093 (1997).

  42. 42.

    Melino, S., Santone, C., Di Nardo, P. & Sarkar, B. Histatins: salivary peptides with copper(II)- and zinc(II)-binding motifs: perspectives for biomedical applications. FEBS J. 281, 657–672 (2014).

  43. 43.

    Goldstein, E. J. C., Citron, D. M., Tyrrell, K. L. & Leoncio, E. S. In vitro activity of pexiganan and 10 comparator antimicrobials against 234 isolates, including 93 Pasteurella species and 50 anaerobic bacterial isolates recovered from animal bite wounds. Antimicrob Agents Chemother. 61, e00246-17 (2017).

  44. 44.

    Mylonakis, E., Podsiadlowski, L., Muhammed, M. & Vilcinskas, A. Diversity, evolution and medical applications of insect antimicrobial peptides. Phil. Trans. R. Soc. Lond. B Biol. Sci. https://doi.org/10.1098/rstb.2015.0290 (2016).

  45. 45.

    Destoumieux-Garzon, D. et al. Antimicrobial peptides in marine invertebrate health and disease. Phil. Trans. R. Soc. Lond. B Biol. Sci. https://doi.org/10.1098/rstb.2015.0300 (2016).

  46. 46.

    Shafee, T. M., Lay, F. T., Hulett, M. D. & Anderson, M. A. The defensins consist of two independent, convergent protein superfamilies. Mol. Biol. Evol. 33, 2345–2356 (2016).

  47. 47.

    Shafee, T. M., Lay, F. T., Phan, T. K., Anderson, M. A. & Hulett, M. D. Convergent evolution of defensin sequence, structure and function. Cell Mol. Life Sci. 74, 663–682 (2017).

  48. 48.

    Vriens, K., Cammue, B. P. & Thevissen, K. Antifungal plant defensins: mechanisms of action and production. Molecules 19, 12280–12303 (2014).

  49. 49.

    Haney, E. F., Mansour, S. C., Hilchie, A. L., de la Fuente-Nunez, C. & Hancock, R. E. High throughput screening methods for assessing antibiofilm and immunomodulatory activities of synthetic peptides. Peptides 71, 276–285 (2015).

  50. 50.

    de la Fuente-Nunez, C., Cardoso, M. H., de Souza Candido, E., Franco, O. L. & Hancock, R. E. Synthetic antibiofilm peptides. Biochim. Biophys. Acta 1858, 1061–1069 (2016).

  51. 51.

    Hilpert, K., Winkler, D. F. & Hancock, R. E. Peptide arrays on cellulose support: SPOT synthesis, a time and cost efficient method for synthesis of large numbers of peptides in a parallel and addressable fashion. Nat. Protoc. 2, 1333–1349 (2007).

  52. 52.

    Niyonsaba, F., Someya, A., Hirata, M., Ogawa, H. & Nagaoka, I. Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and LL-37 on histamine release and prostaglandin D2 production from mast cells. Eur. J. Immunol. 31, 1066–1075 (2001).

  53. 53.

    Chen, X. et al. Antimicrobial peptides human β-defensin (hBD)-3 and hBD-4 activate mast cells and increase skin vascular permeability. Eur. J. Immunol. 37, 434–444 (2007).

  54. 54.

    Scott, M. G. et al. An anti-infective peptide that selectively modulates the innate immune response. Nat. Biotechnol. 25, 465–472 (2007). The first study to demonstrate the ability of a synthetic IDR peptide to control bacterial infections, including methicillin-resistant S. aureus and vancomycin-resistant Enterococcus infections, in preclinical models.

  55. 55.

    Rivas-Santiago, B. et al. Ability of innate defence regulator peptides IDR-1002, IDR-HH2 and IDR-1018 to protect against mycobacterium tuberculosis infections in animal models. PLoS One 8, e59119 (2013).

  56. 56.

    Achtman, A. H. et al. Effective adjunctive therapy by an innate defense regulatory Peptide in a preclinical model of severe malaria. Sci. Transl Med. 4, 135ra164 (2012). The first study to demonstrate effective adjuvant therapeutic potential of a IDR peptide with existing drugs in a parasitic infection model.

  57. 57.

    Nijnik, A. et al. Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J. Immunol. 184, 2539–2550 (2010).

  58. 58.

    Mansour, S. C., de la Fuente-Nunez, C. & Hancock, R. E. Peptide IDR-1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections. J. Pept. Sci. 21, 323–329 (2015).

  59. 59.

    Wuerth, K. C., Falsafi, R. & Hancock, R. E. W. Synthetic host defense peptide IDR-1002 reduces inflammation in Pseudomonas aeruginosa lung infection. PLoS One 12, e0187565 (2017).

  60. 60.

    Hou, M. et al. Antimicrobial peptide LL-37 and IDR-1 ameliorate MRSA pneumonia in vivo. Cell Physiol. Biochem. 32, 614–623 (2013).

  61. 61.

    Cao, D. et al. CpG oligodeoxynucleotide synergizes innate defense regulator peptide for enhancing the systemic and mucosal immune responses to pseudorabies attenuated virus vaccine in piglets in vivo. Int. Immunopharmacol. 11, 748–754 (2011).

  62. 62.

    Kindrachuk, J. et al. A novel vaccine adjuvant comprised of a synthetic innate defence regulator peptide and CpG oligonucleotide links innate and adaptive immunity. Vaccine 27, 4662–4671 (2009).

  63. 63.

    Prysliak, T. et al. Induction of a balanced IgG1/IgG2 immune response to an experimental challenge with Mycoplasma bovis antigens following a vaccine composed of Emulsigen, IDR peptide1002, and poly I:C. Vaccine 35, 6604–6610 (2017).

  64. 64.

    Prysliak, T. & Perez-Casal, J. Immune responses to Mycoplasma bovis proteins formulated with different adjuvants. Can. J. Microbiol. 62, 492–504 (2016).

  65. 65.

    Wu, B. C., Lee, A. H. & Hancock, R. E. W. Mechanisms of the innate defense regulator peptide-1002 anti-inflammatory activity in a sterile inflammation mouse model. J. Immunol. 199, 3592–3603 (2017).

  66. 66.

    Hoeksema, M., van Eijk, M., Haagsman, H. P. & Hartshorn, K. L. Histones as mediators of host defense, inflammation and thrombosis. Future Microbiol. 11, 441–453 (2016).

  67. 67.

    Urban, C. F. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against candida albicans. PLoS Pathog. 5, e1000639 (2009).

  68. 68.

    Donovan, S. M. The role of lactoferrin in gastrointestinal and immune development and function: a preclinical perspective. J. Pediatr. 173, S16–S28 (2016).

  69. 69.

    Bruni, N. et al. Antimicrobial activity of lactoferrin-related peptides and applications in human and veterinary medicine. Molecules 21, 752 (2016).

  70. 70.

    Lehrer, R. I., Cole, A. M. & Selsted, M. E. θ-defensins: cyclic peptides with endless potential. J. Biol. Chem. 287, 27014–27019 (2012).

  71. 71.

    Forde, E. B. et al. Using disease-associated enzymes to activate antimicrobial peptide prodrugs. Methods Mol. Biol. 1548, 359–368 (2017).

  72. 72.

    Pane, K. et al. Antimicrobial potency of cationic antimicrobial peptides can be predicted from their amino acid composition: application to the detection of “cryptic” antimicrobial peptides. J. Theor. Biol. 419, 254–265 (2017).

  73. 73.

    Gaglione, R. et al. Novel human bioactive peptides identified in apolipoprotein B: evaluation of their therapeutic potential. Biochem. Pharmacol. 130, 34–50 (2017).

  74. 74.

    Tucker, A. T. et al. Discovery of next-generation antimicrobials through bacterial self-screening of surface-displayed peptide libraries. Cell 172, 618–628 e613 (2018).

  75. 75.

    Torres, M. D. T., Sothiselvam, S., Lu, T. K. & de la Fuente-Nunez, C. Peptide design principles for antimicrobial applications. J. Mol. Biol. 431, 3547–3567 (2019).

  76. 76.

    Jenssen, H., Hamill, P. & Hancock, R. E. Peptide antimicrobial agents. Clin. Microbiol. Rev. 19, 491–511 (2006).

  77. 77.

    Veldhuizen, E. J., Brouwer, E. C., Schneider, V. A. & Fluit, A. C. Chicken cathelicidins display antimicrobial activity against multiresistant bacteria without inducing strong resistance. PLoS One 8, e61964 (2013).

  78. 78.

    Grein, F., Schneider, T. & Sahl, H. G. Docking on lipid II—a widespread mechanism for potent bactericidal activities of antibiotic peptides. J. Mol. Biol. 431, 3520–3530 (2019).

  79. 79.

    de Leeuw, E. et al. Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett. 584, 1543–1548 (2010).

  80. 80.

    Sass, V. et al. Human beta-defensin 3 inhibits cell wall biosynthesis in staphylococci. Infect. Immun. 78, 2793–2800 (2010).

  81. 81.

    Schneider, V. A. F. et al. Imaging the antistaphylococcal activity of CATH-2: mechanism of attack and regulation of inflammatory response. mSphere 2, e00370-17 (2017).

  82. 82.

    Graf, M. et al. Proline-rich antimicrobial peptides targeting protein synthesis. Nat. Prod. Rep. 34, 702–711 (2017).

  83. 83.

    Hanson, M. A. et al. Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach. eLife 8, e44341 (2019). Using a systematic knockout approach, this study demonstrates that CHDP have synergistic, additive and highly specific microbicidal effects in vivo.

  84. 84.

    Coorens, M., Scheenstra, M. R., Veldhuizen, E. J. & Haagsman, H. P. Interspecies cathelicidin comparison reveals divergence in antimicrobial activity, TLR modulation, chemokine induction and regulation of phagocytosis. Sci. Rep. 7, 40874 (2017).

  85. 85.

    Daher, K. A., Selsted, M. E. & Lehrer, R. I. Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60, 1068–1074 (1986).

  86. 86.

    Tripathi, S., Verma, A., Kim, E. J., White, M. R. & Hartshorn, K. L. LL-37 modulates human neutrophil responses to influenza a virus. J. Leukoc. Biol. 96, 931–938 (2014).

  87. 87.

    Holthausen, D. J. et al. An amphibian host defense peptide is virucidal for human H1 hemagglutinin-bearing influenza viruses. Immunity 46, 587–595 (2017).

  88. 88.

    Kota, S. et al. 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 (2008).

  89. 89.

    Currie, S. M. et al. The human cathelicidin LL-37 has antiviral activity against respiratory syncytial virus. PLoS One 8, e73659 (2013).

  90. 90.

    Currie, S. M. et al. Cathelicidins have direct antiviral activity against respiratory syncytial virus in vitro and protective function in vivo in mice and humans. J. Immunol. 196, 2699–2710 (2016).

  91. 91.

    Harcourt, J. L. et al. Human cathelicidin, LL-37, inhibits respiratory syncytial virus infection in polarized airway epithelial cells. BMC Res. Notes 9, 11 (2016).

  92. 92.

    Howell, M. D. et al. Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J. Immunol. 172, 1763–1767 (2004).

  93. 93.

    Dean, R. E. et al. A carpet-based mechanism for direct antimicrobial peptide activity against vaccinia virus membranes. Peptides 31, 1966–1972 (2010).

  94. 94.

    Brice, D. C., Toth, Z. & Diamond, G. LL-37 disrupts the Kaposi’s sarcoma-associated herpesvirus envelope and inhibits infection in oral epithelial cells. Antivir. Res. 158, 25–33 (2018).

  95. 95.

    Schogler, A. et al. Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. Eur. Respir. J. 47, 520–530 (2016).

  96. 96.

    Sousa, F. H. et al. Cathelicidins display conserved direct antiviral activity towards rhinovirus. Peptides 95, 76–83 (2017).

  97. 97.

    Bastian, A. & Schafer, H. Human alpha-defensin 1 (HNP-1) inhibits adenoviral infection in vitro. Regul. Pept. 101, 157–161 (2001).

  98. 98.

    Smith, J. G. & Nemerow, G. R. Mechanism of adenovirus neutralization by Human alpha-defensins. Cell Host Microbe 3, 11–19 (2008).

  99. 99.

    Smith, J. G. et al. Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization. PLoS Pathog. 6, e1000959 (2010).

  100. 100.

    Tenge, V. R., Gounder, A. P., Wiens, M. E., Lu, W. & Smith, J. G. Delineation of interfaces on human alpha-defensins critical for human adenovirus and human papillomavirus inhibition. PLoS Pathog. 10, e1004360 (2014).

  101. 101.

    Nguyen, E. K., Nemerow, G. R. & Smith, J. G. Direct evidence from single-cell analysis that human {alpha}-defensins block adenovirus uncoating to neutralize infection. J. Virol. 84, 4041–4049 (2010).

  102. 102.

    Hazrati, E. et al. Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection. J. Immunol. 177, 8658–8666 (2006).

  103. 103.

    Wang, A. et al. Enhancement of antiviral activity of human alpha-defensin 5 against herpes simplex virus 2 by arginine mutagenesis at adaptive evolution sites. J. Virol. 87, 2835–2845 (2013).

  104. 104.

    Yasin, B. et al. Theta defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry. J. Virol. 78, 5147–5156 (2004).

  105. 105.

    Brandt, C. R. et al. Evaluation of a theta-defensin in a Murine model of herpes simplex virus type 1 keratitis. Invest. Ophthalmol. Vis. Sci. 48, 5118–5124 (2007).

  106. 106.

    Lehrer, R. I. et al. Multivalent binding of carbohydrates by the human alpha-defensin, HD5. J. Immunol. 183, 480–490 (2009).

  107. 107.

    Cole, A. M. et al. 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 (2002).

  108. 108.

    Gallo, S. A. et al. Theta-defensins prevent HIV-1 Env-mediated fusion by binding gp41 and blocking 6-helix bundle formation. J. Biol. Chem. 281, 18787–18792 (2006).

  109. 109.

    Wang, W. et al. Activity of alpha- and theta-defensins against primary isolates of HIV-1. J. Immunol. 173, 515–520 (2004).

  110. 110.

    Furci, L., Sironi, F., Tolazzi, M., Vassena, L. & Lusso, P. Alpha-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4. Blood 109, 2928–2935 (2007).

  111. 111.

    Tecle, T., White, M. R., Gantz, D., Crouch, E. C. & Hartshorn, K. L. Human neutrophil defensins increase neutrophil uptake of influenza a virus and bacteria and modify virus-induced respiratory burst responses. J. Immunol. 178, 8046–8052 (2007).

  112. 112.

    Salvatore, M. et al. α-defensin inhibits influenza virus replication by cell-mediated mechanism(s). J. Infect. Dis. 196, 835–843 (2007).

  113. 113.

    Sieczkarski, S. B., Brown, H. A. & Whittaker, G. R. Role of protein kinase C betall in influenza virus entry via late endosomes. J. Virol. 77, 460–469 (2003).

  114. 114.

    Doss, M. et al. Hapivirins and diprovirins: novel theta-defensin analogs with potent activity against influenza A virus. J. Immunol. 188, 2759–2768 (2012).

  115. 115.

    Ryan, L. K. et al. 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 (2011).

  116. 116.

    Barlow, P. G. et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One 6, e25333 (2011). This study demonstrates the antiviral activity of CHDP against influenza virus in vitro and in vivo.

  117. 117.

    Kim, J. Y. Human fungal pathogens: why should we learn? J. Microbiol. 54, 145–148 (2016).

  118. 118.

    Revie, N. M., Iyer, K. R., Robbins, N. & Cowen, L. E. Antifungal drug resistance: evolution, mechanisms and impact. Curr. Opin. Microbiol. 45, 70–76 (2018).

  119. 119.

    Verweij, P. E., Chowdhary, A., Melchers, W. J. & Meis, J. F. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin. Infect. Dis. 62, 362–368 (2016).

  120. 120.

    Parisi, K. et al. The evolution, function and mechanisms of action for plant defensins. Semin. Cell Dev. Biol. 88, 107–118 (2019).

  121. 121.

    Menzel, L. P. et al. 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 (2017).

  122. 122.

    Ordonez, S. R., Amarullah, I. H., Wubbolts, R. W., Veldhuizen, E. J. & Haagsman, H. P. Fungicidal mechanisms of cathelicidins LL-37 and CATH-2 revealed by live-cell imaging. Antimicrob. Agents Chemother. 58, 2240–2248 (2014).

  123. 123.

    Puri, S. & Edgerton, M. How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryot. Cell 13, 958–964 (2014).

  124. 124.

    Delattin, N., Brucker, K., Cremer, K., Cammue, B. P. & Thevissen, K. Antimicrobial peptides as a strategy to combat fungal biofilms. Curr. Top. Med. Chem. 17, 604–612 (2017). This study discusses recent advances using novel CHDP-based peptides to combat fungal biofilms.

  125. 125.

    Chertov, O. et al. 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 (1996).

  126. 126.

    Van Wetering, S. et al. Effect of defensins on interleukin-8 synthesis in airway epithelial cells. Am. J. Physiol. 272, L888–L896 (1997).

  127. 127.

    Yang, D., Chen, Q., Chertov, O. & Oppenheim, J. J. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J. Leukoc. Biol. 68, 9–14 (2000).

  128. 128.

    Choi, K. Y. & Mookherjee, N. Multiple immune-modulatory functions of cathelicidin host defense peptides. Front. Immunol. 3, 149 (2012).

  129. 129.

    Steinstraesser, L., Kraneburg, U., Jacobsen, F. & Al-Benna, S. Host defense peptides and their antimicrobial-immunomodulatory duality. Immunobiology 216, 322–333 (2011).

  130. 130.

    Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat. Immunol. 11, 76–83 (2010).

  131. 131.

    Cullen, T. W. et al. Gut microbiota. antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347, 170–175 (2015).

  132. 132.

    Yoshimura, T. et al. The antimicrobial peptide cramp is essential for colon homeostasis by maintaining microbiota balance. J. Immunol. 200, 2174–2185 (2018).

  133. 133.

    Lee, R. J. et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Invest. 124, 1393–1405 (2014).

  134. 134.

    Madera, L. & Hancock, R. E. Synthetic immunomodulatory peptide IDR-1002 enhances monocyte migration and adhesion on fibronectin. J. Innate Immun. 4, 553–568 (2012).

  135. 135.

    De, Y. et al. 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).

  136. 136.

    Tjabringa, G. S., Ninaber, D. K., Drijfhout, J. W., Rabe, K. F. & Hiemstra, P. S. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int. Arch. Allergy Immunol. 140, 103–112 (2006).

  137. 137.

    Hemshekhar, M., Choi, K. G. & Mookherjee, N. 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 (2018).

  138. 138.

    Mookherjee, N. et al. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 176, 2455–2464 (2006).

  139. 139.

    Yang, D. et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utlizes 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).

  140. 140.

    Holly, M. K., Diaz, K. & Smith, J. G. Defensins in viral infection and pathogenesis. Annu. Rev. Virol. 4, 369–391 (2017).

  141. 141.

    Agier, J., Efenberger, M. & Brzezinska-Blaszczyk, E. Cathelicidin impact on inflammatory cells. Cent. Eur. J. Immunol. 40, 225–235 (2015).

  142. 142.

    Suarez-Carmona, M., Hubert, P., Delvenne, P. & Herfs, M. Defensins: “simple” antimicrobial peptides or broad-spectrum molecules? Cytokine Growth Factor Rev. 26, 361–370 (2015).

  143. 143.

    Kurosaka, K., Chen, Q., Yarovinsky, F., Oppenheim, J. J. & 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).

  144. 144.

    Mookherjee, N. et al. Intracellular receptor for human host defense peptide LL-37 in monocytes. J. Immunol. 183, 2688–2696 (2009).

  145. 145.

    Yu, H. B. et al. Sequestosome-1/p62 is the key intracellular target of innate defense regulator peptide. J. Biol. Chem. 284, 36007–36011 (2009).

  146. 146.

    Zhang, Z. et al. Evidence that cathelicidin peptide LL-37 may act as a functional ligand for CXCR2 on human neutrophils. Eur. J. Immunol. 39, 3181–3194 (2009).

  147. 147.

    Zheng, Y. et al. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. Br. J. Dermatol. 157, 1124–1131 (2007).

  148. 148.

    Malerba, M. et al. Epidermal hepcidin is required for neutrophil response to bacterial infection. J. Clin. Invest. 130, 329–334 (2019).

  149. 149.

    Stephan, A. et al. LL37:DNA complexes provide antimicrobial activity against intracellular bacteria in human macrophages. Immunology 148, 420–432 (2016).

  150. 150.

    Koziel, J. et al. Citrullination alters immunomodulatory function of LL-37 essential for prevention of endotoxin-induced sepsis. J. Immunol. 192, 5363–5372 (2014).

  151. 151.

    Wong, A. et al. A Novel biological role for peptidyl-arginine deiminases: citrullination of cathelicidin LL-37 controls the immunostimulatory potential of cell-free DNA. J. Immunol. 200, 2327–2340 (2018).

  152. 152.

    Kilsgard, O. et al. Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities. Am. J. Respir. Cell Mol. Biol. 46, 240–248 (2012).

  153. 153.

    Beaumont, P. E. et al. Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo. PLoS One 9, e99029 (2014). This study demonstrates that cathelicidins can promote bacterial clearance in vivo, in the absence of direct microbicidal effects, by modulating host cellular inflammatory responses.

  154. 154.

    Alalwani, S. M. et al. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. Eur. J. Immunol. 40, 1118–1126 (2010).

  155. 155.

    Hiemstra, P. S. Epithelial antimicrobial peptides and proteins: their role in host defence and inflammation. Paediatr. Respir. Rev. 2, 306–310 (2001).

  156. 156.

    Yang, D., Biragyn, A., Kwak, L. W. & Oppenheim, J. J. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 23, 291–296 (2002).

  157. 157.

    Biragyn, A. et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298, 1025–1029 (2002).

  158. 158.

    Davidson, D. J. et al. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J. Immunol. 172, 1146–1156 (2004).

  159. 159.

    Tewary, P. et al. β-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 (2013).

  160. 160.

    Funderburg, N. et al. Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2. Proc. Natl Acad. Sci. USA 104, 18631–18635 (2007).

  161. 161.

    Bandholtz, L. et al. Antimicrobial peptide LL-37 internalized by immature human dendritic cells alters their phenotype. Scand. J. Immunol. 63, 410–419 (2006).

  162. 162.

    Findlay, E. G. et al. Exposure to the anti-microbial peptide LL-37 produces dendritic cells optimised for immunotherapy. Oncoimmunology 8, 1608106 (2019). This recent study shows that CHDP can enhance cytotoxic T cell responses to promote tumour clearance in vivo via effects on DC differentiation and function, highlighting adjuvant and immunotherapy potential for cancers.

  163. 163.

    Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

  164. 164.

    Ganguly, D. et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J. Exp. Med. 206, 1983–1994 (2009).

  165. 165.

    Kim, S. H., Kim, Y. N. & Jang, Y. S. Cutting edge: LL-37-mediated formyl peptide receptor-2 signaling in follicular dendritic cells contributes to B cell activation in Peyer’s patch germinal centers. J. Immunol. 198, 629–633 (2017).

  166. 166.

    Severino, P. et al. Cathelicidin-deficient mice exhibit increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture. J. Mol. Med. 95, 995–1003 (2017).

  167. 167.

    Deng, Y. Y., Shamoon, M., He, Y., Bhatia, M. & Sun, J. Cathelicidin-related antimicrobial peptide modulates the severity of acute pancreatitis in mice. Mol. Med. Rep. 13, 3881–3885 (2016).

  168. 168.

    Wehkamp, J., Schmid, M., Fellermann, K. & Stange, E. F. Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn’s disease. J. Leukoc. Biol. 77, 460–465 (2005).

  169. 169.

    Cirioni, O. et al. LL-37 protects rats against lethal sepsis caused by gram-negative bacteria. Antimicrob. Agents Chemother. 50, 1672–1679 (2006).

  170. 170.

    Fukumoto, K. et al. Effect of antibacterial cathelicidin peptide CAP18/LL-37 on sepsis in neonatal rats. Pediatr. Surg. Int. 21, 20–24 (2005).

  171. 171.

    Giacometti, A. et al. The antimicrobial peptide BMAP-28 reduces lethality in mouse models of staphylococcal sepsis. Crit. Care Med. 32, 2485–2490 (2004).

  172. 172.

    Coorens, M. et al. Killing of P. aeruginosa by chicken cathelicidin-2 is immunogenically silent, preventing lung inflammation in vivo. Infect. Immun. 85, e00546-17 (2017). This study demonstrates that chicken cathelicidin CATH-2 kills P. aeruginosa in an immunogenically silent manner and controls lung inflammation in vivo, making a case for the development of CHDP-based anti-infectives with both antimicrobial and immunomodulatory functions.

  173. 173.

    Nagaoka, I. et al. 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 (2001).

  174. 174.

    Rosenfeld, Y., Papo, N. & Shai, Y. Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J. Biol. Chem. 281, 1636–1643 (2006).

  175. 175.

    Molhoek, E. M. et al. Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses. Biol. Chem. 390, 295–303 (2009). The first study to interrogate the sequence–function relationship in the immunomodulatory functions of CHDP.

  176. 176.

    Choi, K. Y., Napper, S. & Mookherjee, N. Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation. Immunology 143, 68–80 (2014).

  177. 177.

    Zhang, Z., Cherryholmes, G. & Shively, J. E. Neutrophil secondary necrosis is induced by LL-37 derived from cathelicidin. J. Leukoc. Biol. 84, 780–788 (2008).

  178. 178.

    Merkle, M. et al. LL37 inhibits the inflammatory endothelial response induced by viral or endogenous DNA. J. Autoimmun. 65, 19–29 (2015).

  179. 179.

    van Dijk, A. et al. Immunomodulatory and anti-inflammatory activities of chicken cathelicidin-2 derived peptides. PLoS One 11, e0147919 (2016).

  180. 180.

    Mookherjee, N. et al. Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide. J. Leukoc. Biol. 80, 1563–1574 (2006).

  181. 181.

    Coorens, M., van Dijk, A., Bikker, F., Veldhuizen, E. J. & Haagsman, H. P. Importance of endosomal cathelicidin degradation to enhance DNA-induced chicken macrophage activation. J. Immunol. 195, 3970–3977 (2015).

  182. 182.

    Coorens, M. et al. Cathelicidins inhibit escherichia coli-induced TLR2 and TLR4 activation in a viability-dependent manner. J. Immunol. 199, 1418–1428 (2017).

  183. 183.

    McHugh, B. J. et al. Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses during infection with Pseudomonas aeruginosa. PLoS Pathogens 15, e1007694 (2019).

  184. 184.

    Semple, F. et al. Human β-defensin 3 affects the activity of pro-inflammatory pathways associated with MyD88 and TRIF. Eur. J. Immunol. 41, 3291–3300 (2011).

  185. 185.

    Semple, F. et al. Human beta-defensin 3 has immunosuppressive activity in vitro and in vivo. Eur. J. Immunol. 40, 1073–1078 (2010).

  186. 186.

    McGlasson, S. L. et al. Human beta-defensin 3 increases the TLR9-dependent response to bacterial DNA. Eur. J. Immunol. 47, 658–664 (2017).

  187. 187.

    Semple, F. et al. Human beta-defensin 3 [corrected] exacerbates MDA5 but suppresses TLR3 responses to the viral molecular pattern mimic polyinosinic:polycytidylic acid. PLoS Genet. 11, e1005673 (2015).

  188. 188.

    Funderburg, N. T. et al. The Toll-like receptor 1/2 agonists Pam3CSK4 and human beta-defensin-3 differentially induce interleukin-10 and nuclear factor-kappaB signalling patterns in human monocytes. Immunology 134, 151–160 (2011).

  189. 189.

    Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl Med. 3, 73ra19 (2011).

  190. 190.

    Filewod, N. C., Pistolic, J. & Hancock, R. E. Low concentrations of LL-37 alter IL-8 production by keratinocytes and bronchial epithelial cells in response to proinflammatory stimuli. FEMS Immunol. Med. Microbiol. 56, 233–240 (2009).

  191. 191.

    Lai, Y. et al. LL37 and cationic peptides enhance TLR3 signaling by viral double-stranded RNAs. PLoS One 6, e26632 (2011).

  192. 192.

    Elssner, A., Duncan, M., Gavrilin, M. & Wewers, M. D. A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J. Immunol. 172, 4987–4994 (2004).

  193. 193.

    Li, N. et al. Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36gamma induction in human epidermal keratinocytes. J. Immunol. 193, 5140–5148 (2014).

  194. 194.

    Yu, J. et al. Host defense peptide LL-37, in synergy with inflammatory mediator IL-1beta, augments immune responses by multiple pathways. J. Immunol. 179, 7684–7691 (2007).

  195. 195.

    Lau, Y. E. et al. Interaction and cellular localization of the human host defense peptide LL-37 with lung epithelial cells. Infect. Immun. 73, 583–591 (2005).

  196. 196.

    Sandgren, S. et al. 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 (2004).

  197. 197.

    Lau, Y. E., Bowdish, D. M., Cosseau, C., Hancock, R. E. & Davidson, D. J. Apoptosis of airway epithelial cells: human serum sensitive induction by the cathelicidin LL-37. Am. J. Respir. Cell Mol. Biol. 34, 399–409 (2006).

  198. 198.

    Barlow, P. G. et al. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am. J. Respir. Cell Mol. Biol. 43, 692–702 (2010).

  199. 199.

    Barlow, P. G. et al. The human cationic host defense peptide LL-37 mediates contrasting effects on apoptotic pathways in different primary cells of the innate immune system. J. Leukoc. Biol. 80, 509–520 (2006).

  200. 200.

    Mader, J. S., Mookherjee, N., Hancock, R. E. & Bleackley, R. C. The human host defense peptide LL-37 induces apoptosis in a calpain- and apoptosis-inducing factor-dependent manner involving Bax activity. Mol. Cancer Res. 7, 689–702 (2009).

  201. 201.

    Bowdish, D. M., Davidson, D. J., Speert, D. P. & Hancock, R. E. The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. J. Immunol. 172, 3758–3765 (2004).

  202. 202.

    Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975 (2002).

  203. 203.

    Li, H. N. et al. Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages. J. Leukoc. Biol. 86, 891–902 (2009).

  204. 204.

    Miles, K. et al. Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins. J. Immunol. 183, 2122–2132 (2009).

  205. 205.

    Nizet, V. et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414, 454–457 (2001).

  206. 206.

    Yu, F. S. et al. Flagellin stimulates protective lung mucosal immunity: role of cathelicidin-related antimicrobial peptide. J. Immunol. 185, 1142–1149 (2010).

  207. 207.

    Huang, L. C., Reins, R. Y., Gallo, R. L. & McDermott, A. M. Cathelicidin-deficient (Cnlp−/−) mice show increased susceptibility to Pseudomonas aeruginosa keratitis. Invest. Ophthalmol. Vis. Sci. 48, 4498–4508 (2007).

  208. 208.

    Iimura, M. et al. Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J. Immunol. 174, 4901–4907 (2005).

  209. 209.

    Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).

  210. 210.

    Kovach, M. A. et al. Cathelicidin-related antimicrobial peptide is required for effective lung mucosal immunity in Gram-negative bacterial pneumonia. J. Immunol. 189, 304–311 (2012).

  211. 211.

    Pachon-Ibanez, M. E., Smani, Y., Pachon, J. & Sanchez-Cespedes, J. Perspectives for clinical use of engineered human host defense antimicrobial peptides. FEMS Microbiol. Rev. 41, 323–342 (2017).

  212. 212.

    Woodburn, K. W., Jaynes, J. M. & Clemens, L. E. Evaluation of the antimicrobial peptide, RP557, for the broad-spectrum treatment of wound pathogens and biofilm. Front. Microbiol. 10, 1688 (2019).

  213. 213.

    Tenland, E. et al. A novel derivative of the fungal antimicrobial peptide plectasin is active against Mycobacterium tuberculosis. Tuberculosis 113, 231–238 (2018).

  214. 214.

    Obuobi, S. et al. Facile and efficient encapsulation of antimicrobial peptides via crosslinked DNA nanostructures and their application in wound therapy. J. Control. Release 313, 120–130 (2019).

  215. 215.

    Riool, M., de Breij, A., Drijfhout, J. W., Nibbering, P. H. & Zaat, S. A. J. Antimicrobial peptides in biomedical device manufacturing. Front. Chem. 5, 63 (2017).

  216. 216.

    de Breij, A. et al. The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms. Sci. Transl Med. 10, eaan4044 (2018).

  217. 217.

    Jiang, Y. et al. Antiviral activity of recombinant mouse beta-defensin 3 against influenza a virus in vitro and in vivo. Antivir. Chem. Chemother. 22, 255–262 (2012).

  218. 218.

    Gong, T. et al. Recombinant mouse beta-defensin 2 inhibits infection by influenza a virus by blocking its entry. Arch. Virol. 155, 491–498 (2010).

  219. 219.

    Li, W. et al. Construction of eukaryotic expression vector with mBD1-mBD3 fusion genes and exploring its activity against influenza a virus. Viruses 6, 1237–1252 (2014).

  220. 220.

    Wohlford-Lenane, C. L. et al. Rhesus theta-defensin prevents death in a mouse model of severe acute respiratory syndrome coronavirus pulmonary disease. J. Virol. 83, 11385–11390 (2009).

  221. 221.

    Greber, K. E. & Dawgul, M. Antimicrobial peptides under clinical trials. Curr. Top. Med. Chem. 17, 620–628 (2017).

  222. 222.

    Wiig, M. E. et al. PXL01 in sodium hyaluronate for improvement of hand recovery after flexor tendon repair surgery: randomized controlled trial. PLoS One 9, e110735 (2014).

  223. 223.

    Gronberg, A., Mahlapuu, M., Stahle, M., Whately-Smith, C. & Rollman, O. 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 (2014). The first randomized clinical trial of a CHDP shown to be effective in hard-to-heal venous leg ulcers.

  224. 224.

    Martineau, A. R. et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. Lancet Respir. Med. 3, 120–130 (2015).

  225. 225.

    Mily, A. et al. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis. BMC Pulm. Med. 13, 23 (2013).

  226. 226.

    Lipsky, B. A., Holroyd, K. J. & Zasloff, M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin. Infect. Dis. 47, 1537–1545 (2008).

  227. 227.

    Bals, R., Weiner, D. J., Moscioni, A. D., Meegalla, R. L. & Wilson, J. M. Augmentation of innate host defense by expression of a cathelicidin antimicrobial peptide. Infect. Immun. 67, 6084–6089 (1999).

  228. 228.

    Cuperus, T., van Dijk, A., Matthijs, M. G., Veldhuizen, E. J. & Haagsman, H. P. Protective effect of in ovo treatment with the chicken cathelicidin analog D-CATH-2 against avian pathogenic E. coli. Sci. Rep. 6, 26622 (2016). The first study to demonstrate that prophylactic cathelicidin treatment of chick embryos in ovo partially protects chickens from E. coli infection 10 days later, thus establishing the use in veterinary medicine.

  229. 229.

    North, J. R. et al. A novel approach for emerging and antibiotic resistant infections: innate defense regulators as an agnostic therapy. J. Biotechnol. 226, 24–34 (2016).

  230. 230.

    Niyonsaba, F. et al. The innate defense regulator peptides IDR-HH2, IDR-1002, and IDR-1018 modulate human neutrophil functions. J. Leukoc. Biol. 94, 159–170 (2013).

  231. 231.

    Tai, E. K. et al. Intrarectal administration of mCRAMP-encoding plasmid reverses exacerbated colitis in Cnlp−/− mice. Gene Ther. 20, 187–193 (2013).

  232. 232.

    Tai, E. K. et al. A new role for cathelicidin in ulcerative colitis in mice. Exp. Biol. Med. 232, 799–808 (2007).

  233. 233.

    Wong, C. C. et al. Protective effects of cathelicidin-encoding Lactococcus lactis in murine ulcerative colitis. J. Gastroenterol. Hepatol. 27, 1205–1212 (2012).

  234. 234.

    Hing, T. C. et al. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut 62, 1295–1305 (2013).

  235. 235.

    Otvos, L. Host defense peptides and cancer; perspectives on research design and outcomes. Protein Pept. Lett. 24, 879–886 (2017).

  236. 236.

    Wu, W. K. et al. Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int. J. Cancer 127, 1741–1747 (2010).

  237. 237.

    Roudi, R., Syn, N. L. & Roudbary, M. Antimicrobial peptides as biologic and immunotherapeutic agents against cancer: a comprehensive overview. Front. Immunol. 8, 1320 (2017).

  238. 238.

    Schulze, K., Ebensen, T., Babiuk, L. A., Gerdts, V. & Guzman, C. A. Intranasal vaccination with an adjuvanted polyphosphazenes nanoparticle-based vaccine formulation stimulates protective immune responses in mice. Nanomedicine 13, 2169–2178 (2017).

  239. 239.

    Garlapati, S. et al. Immunization with PCEP microparticles containing pertussis toxoid, CpG ODN and a synthetic innate defense regulator peptide induces protective immunity against pertussis. Vaccine 29, 6540–6548 (2011).

  240. 240.

    Yu, C. H. et al. Synthetic innate defense regulator peptide combination using CpG ODN as a novel adjuvant induces longlasting and balanced immune responses. Mol. Med. Rep. 13, 915–924 (2016).

  241. 241.

    Sorensen, O. E. et al. Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J. Immunol. 170, 5583–5589 (2003).

  242. 242.

    Baroni, A. et al. Antimicrobial human beta-defensin-2 stimulates migration, proliferation and tube formation of human umbilical vein endothelial cells. Peptides 30, 267–272 (2009).

  243. 243.

    Carretero, M. et al. In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J. Invest. Dermatol. 128, 223–236 (2008).

  244. 244.

    Koczulla, R. et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J. Clin. Invest. 111, 1665–1672 (2003).

  245. 245.

    Arampatzioglou, A. et al. Clarithromycin enhances the antibacterial activity and wound healing capacity in type 2 diabetes mellitus by increasing LL-37 load on neutrophil extracellular traps. Front. Immunol. 9, 2064 (2018).

  246. 246.

    Wang, B. et al. IL-1beta-induced protection of keratinocytes against Staphylococcus aureus-secreted proteases is mediated by human beta-defensin 2. J. Invest. Dermatol. 137, 95–105 (2017).

  247. 247.

    Heilborn, J. D. et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120, 379–389 (2003).

  248. 248.

    Dutta, D. et al. Development of silicone hydrogel antimicrobial contact lenses with Mel4 peptide coating. Optom. Vis. Sci. 95, 937–946 (2018).

  249. 249.

    van Dijk, A., Hedegaard, C. J., Haagsman, H. P. & Heegaard, P. M. H. The potential for immunoglobulins and host defense peptides (HDPs) to reduce the use of antibiotics in animal production. Vet. Res. 49, 68 (2018).

  250. 250.

    Zimmer, J., Hobkirk, J., Mohamed, F., Browning, M. J. & Stover, C. M. On the functional overlap between complement and anti-microbial peptides. Front. Immunol. 5, 689 (2014).

  251. 251.

    Bucki, R., Sostarecz, A. G., Byfield, F. J., Savage, P. B. & Janmey, P. A. Resistance of the antibacterial agent ceragenin CSA-13 to inactivation by DNA or F-actin and its activity in cystic fibrosis sputum. J. Antimicrob. Chemother. 60, 535–545 (2007).

  252. 252.

    Pezzulo, A. A. et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 487, 109–113 (2012).

  253. 253.

    Mallia, P. et al. Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 186, 1117–1124 (2012).

  254. 254.

    Mercer, D. K. et al. Improved methods for assessing therapeutic potential of antifungal agents against dermatophytes and their application in the development of NP213, a novel onychomycosis therapy candidate. Antimicrob Agents Chemother. 63, e02117-18 (2019).

  255. 255.

    Sakoulas, G., Kumaraswamy, M., Kousha, A. & Nizet, V. Interaction of antibiotics with innate host defense factors against Salmonella enterica serotype Newport. mSphere. 2, e00410-17 (2017).

  256. 256.

    Le, J. et al. Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur. J. Clin. Microbiol. Infect. Dis. 35, 1441–1447 (2016).

  257. 257.

    Kumaraswamy, M. et al. Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR Stenotrophomonas maltophilia. J. Antimicrob. Chemother. 71, 1264–1269 (2016). This study demonstrates antibiotic synergy with CHDP, thus establishing the potential of novel therapeutic cocktails, showing that antibiotic function is affected by native CHDP expression levels and making the case for the need for new approaches to minimum inhibitory concentration testing.

  258. 258.

    Lin, L. et al. Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. EBioMedicine 2, 690–698 (2015).

  259. 259.

    Peric, M. et al. Vitamin D analogs differentially control antimicrobial peptide/“alarmin” expression in psoriasis. PLoS One 4, e6340 (2009).

  260. 260.

    Sato-Deguchi, E. et al. Topical vitamin D3 analogues induce thymic stromal lymphopoietin and cathelicidin in psoriatic skin lesions. Br. J. Dermatol. 167, 77–84 (2012).

  261. 261.

    Peng, L. H. et al. Integration of antimicrobial peptides with gold nanoparticles as unique non-viral vectors for gene delivery to mesenchymal stem cells with antibacterial activity. Biomaterials 103, 137–149 (2016).

  262. 262.

    Casciaro, B. et al. Gold-nanoparticles coated with the antimicrobial peptide esculentin-1a(1-21)NH2 as a reliable strategy for antipseudomonal drugs. Acta Biomater. 47, 170–181 (2017).

  263. 263.

    Piotrowska, U., Sobczak, M. & Oledzka, E. Current state of a dual behaviour of antimicrobial peptides-therapeutic agents and promising delivery vectors. Chem. Biol. Drug Des. 90, 1079–1093 (2017).

  264. 264.

    Cao, J. et al. Yeast-based synthetic biology platform for antimicrobial peptide production. ACS Synth. Biol. 7, 896–902 (2018).

  265. 265.

    Wibowo, D. & Zhao, C. X. Recent achievements and perspectives for large-scale recombinant production of antimicrobial peptides. Appl. Microbiol. Biotechnol. 103, 659–671 (2019).

  266. 266.

    Andersson, D. I., Hughes, D. & Kubicek-Sutherland, J. Z. Mechanisms and consequences of bacterial resistance to antimicrobial peptides. Drug Resist. Updat. 26, 43–57 (2016).

  267. 267.

    Joo, H. S., Fu, C. I. & Otto, M. Bacterial strategies of resistance to antimicrobial peptides. Phil. Trans. R. Soc. Lond. B Biol. Sci. https://doi.org/10.1098/rstb.2015.0292 (2016).

  268. 268.

    Sahl, H. G. & Shai, Y. Bacterial resistance to antimicrobial peptides. Biochim. Biophys. Acta 1848, 3019–3020 (2015).

  269. 269.

    El Shazely, B., Urbanski, A., Johnston, P. R. & Rolff, J. In vivo exposure of insect AMP resistant staphylococcus aureus to an insect immune system. Insect Biochem. Mol. Biol. 110, 60–68 (2019). This study discusses the aspects of bacterial resistance to CHDP, and demonstrates that resistance generated to CHDP in the laboratory provides no survival advantage to the bacteria in an insect host environment that is dominated by antimicrobial peptides.

  270. 270.

    Tsomaia, N. Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem. 94, 459–470 (2015).

  271. 271.

    Kintses, B. et al. Phylogenetic barriers to horizontal transfer of antimicrobial peptide resistance genes in the human gut microbiota. Nat. Microbiol. 4, 447–458 (2019).

  272. 272.

    Swidergall, M. & Ernst, J. F. Interplay between candida albicans and the antimicrobial peptide armory. Eukaryot. Cell 13, 950–957 (2014).

  273. 273.

    Nakatsuji, T. et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med. 9, eaah4680 (2017).

  274. 274.

    Doss, M. et al. Interactions of alpha-, beta-, and theta-defensins with influenza a virus and surfactant protein D. J. Immunol. 182, 7878–7887 (2009).

  275. 275.

    Leikina, E. et al. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat. Immunol. 6, 995–1001 (2005).

  276. 276.

    Tripathi, S. et al. The human cathelicidin LL-37 inhibits influenza a viruses through a mechanism distinct from that of surfactant protein D or defensins. J. Gen. Virol. 94, 40–49 (2013).

  277. 277.

    Openshaw, P. J. M., Chiu, C., Culley, F. J. & Johansson, C. Protective and harmful Immunity to RSV infection. Annu. Rev. Immunol. 35, 501–532 (2017).

  278. 278.

    Wiens, M. E. & Smith, J. G. α-defensin HD5 inhibits human papillomavirus 16 infection via capsid stabilization and redirection to the lysosome. mBio 8, e02304-16 (2017).

  279. 279.

    Zhang, L., Lopez, P., He, T., Yu, W. & Ho, D. D. Retraction of an interpretation. Science 303, 467 (2004).

  280. 280.

    Demirkhanyan, L. H. et al. Multifaceted mechanisms of HIV-1 entry inhibition by human alpha-defensin. J. Biol. Chem. 287, 28821–28838 (2012).

  281. 281.

    Wu, Z. et al. Human neutrophil alpha-defensin 4 inhibits HIV-1 infection in vitro. FEBS Lett. 579, 162–166 (2005).

  282. 282.

    Chang, T. L., Vargas, J. Jr., DelPortillo, A. & Klotman, M. E. Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. J. Clin. Invest. 115, 765–773 (2005).

  283. 283.

    Munk, C. et al. The theta-defensin, retrocyclin, inhibits HIV-1 entry. AIDS Res. Hum. Retroviruses 19, 875–881 (2003).

  284. 284.

    Owen, S. M. et al. RC-101, a retrocyclin-1 analogue with enhanced activity against primary HIV type 1 isolates. AIDS Res. Hum. Retroviruses 20, 1157–1165 (2004).

  285. 285.

    Cole, A. L. et al. HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of gp41. J. Immunol. 176, 6900–6905 (2006).

  286. 286.

    Sun, L. et al. Human beta-defensins suppress human immunodeficiency virus infection: potential role in mucosal protection. J. Virol. 79, 14318–14329 (2005).

  287. 287.

    Lafferty, M. K., Sun, L., Christensen-Quick, A., Lu, W. & Garzino-Demo, A. Human beta defensin 2 selectively inhibits HIV-1 in highly permissive CCR6+CD4+ T cells. Viruses 9, 111 (2017).

  288. 288.

    Quinones-Mateu, M. E. et al. Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication. AIDS 17, F39–F48 (2003).

  289. 289.

    Bergman, P., Walter-Jallow, L., Broliden, K., Agerberth, B. & Soderlund, J. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr. HIV Res. 5, 410–415 (2007).

  290. 290.

    Wong, J. H. et al. Effects of cathelicidin and its fragments on three key enzymes of HIV-1. Peptides 32, 1117–1122 (2011).

  291. 291.

    He, M. et al. Cathelicidin-derived antimicrobial peptides inhibit Zika virus through direct inactivation and interferon pathway. Front. Immunol. 9, 722 (2018).

Download references

Acknowledgements

N.M. is supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council Canada for peptide research. M.A.A. is supported by the Australian Research Council. H.P.H. is supported by NWO-ZonMW and NWO-TTW Perspectief grants. D.J.D. is supported by the British Skin Foundation (026/s/17), Action Medical Research (GN2703) and the Chief Scientist Office (TCS/18/02). The authors also gratefully acknowledge Y. Gasper and M. Bleackley, La Trobe University, for their assistance with tables and figures.

Author information

Correspondence to Neeloffer Mookherjee.

Ethics declarations

Competing interests

N.M. is listed as an inventor on patents related to immunomodulatory aspects of host defence peptides and IDR peptides. M.A.A. is Chief Scientific Officer and Director of the start-up company Hexima, which has a cationic antimicrobial peptide in clinical trials for treatment of onychomycosis. H.P.H. owns stock in the start-up company Celestial Therapeutics Inc. and has patents on antimicrobial peptide therapeutics licensed to Zoetis. D.J.D. declares no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Dramp Database: http://dramp.cpu-bioinfor.org/browse/ClinicalTrialsData.php

Glossary

Host defence peptides

Naturally occurring typically amphipathic cationic peptides that modulate host immune responses to control infection and regulate inflammation (commonly used as an alternative name for antimicrobial peptides to encompass all their functions).

Antimicrobial peptides

Naturally occurring cationic peptides, typically shorter than 50 amino acids in length, with the ability to kill microorganisms.

Defensins

A family of host defence peptides with a common β-sheet core stabilized with three or four disulfide bridges depending on the source.

Cathelicidin

A member of a family of host defence peptides named after the conserved cathelin-like domain in the propeptide precursor.

Histatins

A family of histidine-rich host defence peptides.

Peptidomimetics

Compounds that mimic a natural peptide and retain the biological function of the parent protein.

Innate defence regulator peptides

(IDR peptides). Small synthetic cationic peptides with immunomodulatory functions, derived from natural host defence peptides.

Cryptic peptides

Segments of secreted proteins identified by bioinformatics screening to potentially function as antimicrobial peptides.

Immune homeostasis

Balanced and tightly regulated immune response under physiologically normal conditions.

Immunomodulation

The process of activating, suppressing or altering the nature of immune function.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mookherjee, N., Anderson, M.A., Haagsman, H.P. et al. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-019-0058-8

Download citation