Defensin

Monomeric and dimeric structures of human beta-defensin HBD-2

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They have also been reported in plants.[1][2] They are, and function as, host defense peptides. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. They consist of 18-45 amino acids including six (in vertebrates) to eight conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytosed bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.

Defensins are antimicrobial peptides that act mainly by disrupting the structure of bacterial cell membranes and are found in many compartments of the body. Evidence is accumulating that defensins play a central role in defense against pathogens, and they are considered as a part of the innate immune response.[3] They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds presents in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborn against pathogens with which they may come in contact.[4][5]

Varieties

The name 'defensin' was coined in the mid1980s, though the proteins had been studied as 'Cationic Antimicrobial Proteins'.[6] The underlying genes responsible for defensin production are highly polymorphic. Some aspects are conserved, however; the hallmarks of a β-defensin are its small size, high density of cationic charge, and six-cysteine-residue motif. In general, they are encoded by two-exon genes, wherein the first exon encodes for a hydrophobic leader sequence and the second for a peptide containing the cysteine motif. All defensins have disulfide linkages. The disulfide linkages have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity.[7][8]

The mammalian defensins (Table below) are different from arthropod defensins. The latter are more similar to protein scorpion toxins.[9] Subsequent investigations confirmed relationships between scorpion toxins that block potassium channels and insect defensins in their three-dimensional structure and their disruption of membrane functions of invasive microbes. Experimental deletion of a small loop of a defensin molecule from a Hymenopteran parasitoid venom that shares attributes of scorpion toxin, removed steric hindrance of interactions between peptides and channels. The resulting peptide was neurotoxin that selectively inhibited potassium channels, binding to the channels in the same manner as scorpion toxins. The results presented structural and functional evidence for the basis of toxin evolution.[10]

Theta defensins form a single beta hairpin structure and therefore also represent a distinct group.

Type Gene Symbol Gene Name Protein Name Description
α-defensins DEFA1 Defensin, alpha 1 Neutrophil defensin 1 Are expressed primarily in neutrophils as well as in NK cells and certain T-lymphocyte subsets. DEFA5 and DEFA6 are expressed in Paneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
DEFA1B Defensin, alpha 1B Defensin, alpha 1
DEFA3 Defensin, alpha 3, neutrophil-specific Neutrophil defensin 3
DEFA4 Defensin, alpha 4, corticostatin Neutrophil defensin 4
DEFA5 Defensin, alpha 5, Paneth cell-specific Defensin-5
DEFA6 Defensin, alpha 6, Paneth cell-specific Defensin-6
β-defensins DEFB1 Defensin, beta 1 Beta-defensin 1 Are the most widely distributed, being secreted by leukocytes and epithelial cells of many kinds. For example, they can be found on the tongue, skin, cornea, salivary glands, kidneys, esophagus, and respiratory tract. It has been suggested (but also challenged) that some of the pathology of cystic fibrosis arises from the inhibition of β-defensin activity on the epithelial surfaces of the lungs and trachea due to higher salt content.
DEFB2 Defensin, beta 2 Beta-defensin 2
DEFB103A Defensin, beta 103B Beta-defensin 103
... ... ...
DEFB106A Defensin, beta 106A Beta-defensin 106A
DEFB106B Defensin, beta 106B Beta-defensin 106B
DEFB107B Defensin, beta 107A Beta-defensin 107
DEFB110 Defensin, beta 110 Beta-defensin 110
... ... ...
DEFB136 Defensin, beta 136 Beta-defensin 136
θ-defensins DEFT1P Defensin, theta 1 pseudogene not expressed in humans Are rare, and thus far have been found only in the leukocytes of the rhesus macaque[11] and the olive baboon, Papio anubis, being vestigial in humans and other primates.[12][13]

Function

In immature marsupials, because their immune system is underdeveloped at the time of birth, defensins play a major role in defense against pathogens. They are produced in the milk of the mother as well as by the young marsupial in question.

In human breast milk, defensin play a central role in neonate immunity[14]

Human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin,[15] retrocyclin, was created by `fixing' the pseudogene, and it was shown to be effective against HIV[16] and other viruses, including herpes simplex virus and influenza A. They act primarily by preventing these viruses from entering their target cells.

Also interesting is the effect of alpha-defensins on the exotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces a metalloprotease Lethal Factor (LF) protein to target MAPKK, is vulnerable to human neutrophil protein-1 (HNP-1). This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.[17]

Defensin-like proteins are also a component of platypus venom.

Pathology

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.[18]

An imbalance of defensins in the skin may contribute to acne.[19]

A reduction of ileal defensins may predispose to Crohn's disease.[20][21]

In one small study, a significant increase in alpha defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.[22]

Defensins are found in the human skin during inflammatory conditions like psoriasis[23] and also during wound healing.

Defensin-mimetics as antibiotics, antifungals, and anti-inflammatories

Defensin-Mimetics, also called host defense peptide (HDP) mimetics, developed at the University of Pennsylvania, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity.[24] Similar molecules (e.g. Brilacidin formerly PMX-30063) are being developed as antibiotics,[25] anti-inflammatories for Oral Mucositis,[26][27] and antifungals, especially for Candidiasis.[28][29][30]

See also

References

Wikimedia Commons has media related to Defensins.
  1. ↑ "Structure–activity studies of AtPep1, a plant peptide signal involved in the innate immune response". Peptides. 29: 2083–2089. doi:10.1016/j.peptides.2008.08.019.
  2. ↑ "Plant defensins". Planta. 216: 193–202. 2002. doi:10.1007/s00425-002-0902-6. PMID 12447532.
  3. ↑ Barrera, G. J., Sanchez, G., & Gonzalez, J. E. (2012). Trefoil factor 3 isolated from human breast milk downregulates cytokines (IL8 and IL6) and promotes human beta defensin (hBD2 and hBD4) expression in intestinal epithelial cells HT-29. Bosnian journal of basic medical sciences/Udruzenje basicnih mediciniskih znanosti= Association of Basic Medical Sciences, 12(4), 256-264.
  4. ↑ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
  5. ↑ Barrera, G. J., Sanchez, G., & Gonzalez, J. E. (2012). Trefoil factor 3 isolated from human breast milk downregulates cytokines (IL8 and IL6) and promotes human beta defensin (hBD2 and hBD4) expression in intestinal epithelial cells HT-29. Bosnian journal of basic medical sciences/Udruzenje basicnih mediciniskih znanosti= Association of Basic Medical Sciences, 12(4), 256-264.
  6. ↑ Nature timeline of discovery of definsins
  7. ↑ Varkey, Jobin; Singh, Shashi; Nagaraj, Ramakrishnan (November 2006). "Antibacterial activity of linear peptides spanning the carboxy-terminal β-sheet domain of arthropod defensins". Peptides. 27 (11): 2614–2623. doi:10.1016/j.peptides.2006.06.010.
  8. ↑ Varkey, J.; Nagaraj, R. (26 October 2005). "Antibacterial Activity of Human Neutrophil Defensin HNP-1 Analogs without Cysteines". Antimicrobial Agents and Chemotherapy. 49 (11): 4561–4566. doi:10.1128/AAC.49.11.4561-4566.2005.
  9. ↑ Shunyi Zhu, Wenxin Li, Dahe Jiang, and Xianchun Zeng. Evidence for the Existence of Insect defensin-like Peptide in Scorpion Venom" IUBMB Life 50: 57–61, 2000
  10. ↑ Shunyi Zhu, Steve Peigneur, Bin Gao, Yoshitaka Umetsu, Shinya Ohki, Jan Tytgat. Experimental Conversion of a Defensin into a Neurotoxin: Implications for Origin of Toxic Function. Mol Biol Evol (2014) doi:10.1093/molbev/msu038
  11. ↑ Tran D, Tran P, Roberts K, Osapay G, Schaal J, Ouellette A, Selsted ME (March 2008). "Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins". Antimicrob. Agents Chemother. 52 (3): 944–53. doi:10.1128/AAC.01090-07. PMC 2258523Freely accessible. PMID 18160518.
  12. ↑ Angie Eva Garcia and Michael Selsted Olive baboon theta-defensins FASEB J. 2008 22:673.11
  13. ↑ Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME (December 2008). "Isolation, synthesis, and antimicrobial activities of naturally occurring theta-defensin isoforms from baboon leukocytes". Infect. Immun. 76 (12): 5883–91. doi:10.1128/IAI.01100-08. PMC 2583559Freely accessible. PMID 18852242.
  14. ↑ Barrera, G. J., Sanchez, G., & Gonzalez, J. E. (2012). Trefoil factor 3 isolated from human breast milk downregulates cytokines (IL8 and IL6) and promotes human beta defensin (hBD2 and hBD4) expression in intestinal epithelial cells HT-29. Bosnian journal of basic medical sciences/Udruzenje basicnih mediciniskih znanosti= Association of Basic Medical Sciences, 12(4), 256-264.
  15. ↑ retrocyclin at the US National Library of Medicine Medical Subject Headings (MeSH)
  16. ↑ Münk C, Wei G, Yang OO, et al. (October 2003). "The theta-defensin, retrocyclin, inhibits HIV-1 entry". AIDS Res. Hum. Retroviruses. 19 (10): 875–81. doi:10.1089/088922203322493049. PMID 14585219.
  17. ↑ Kim C, Gajendran N, Mittrücker H, Weiwad M, Song Y, Hurwitz R, Wilmanns M, Fischer G, Kaufmann S (2005). "Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences". Proc Natl Acad Sci U S A. 102 (13): 4830–5. doi:10.1073/pnas.0500508102. PMC 555714Freely accessible. PMID 15772169.
  18. ↑ Albrethsen J; Bøgebo, R; Gammeltoft, S; Olsen, J; Winther, B; Raskov, H (2005). "Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study". BMC Cancer. 5: 9. doi:10.1186/1471-2407-5-8. PMC 548152Freely accessible. PMID 15656915.
  19. ↑ Philpott M (2003). "Defensins and acne". Mol Immunol. 40 (7): 457–62. doi:10.1016/S0161-5890(03)00154-8. PMID 14568392.
  20. ↑ Genomics & Genetics Weekly, "Researchers discover a possible cause of chronic inflammations of Crohn Disease." August 11, 2006, page 72
  21. ↑ Wehkamp J, et al. (2005). "Reduced Paneth cell alpha-defensins in ileal Crohn's disease" (abstract). Proc Natl Acad Sci U S A. 102 (50): 18129–34. doi:10.1073/pnas.0505256102. PMC 1306791Freely accessible. PMID 16330776.
  22. ↑ Craddock RM, Huang JT, Jackson E, et al. (March 2008). "Increased alpha defensins as a blood marker for schizophrenia susceptibility". Mol. Cell Proteomics. 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140.
  23. ↑ Harder, J; Bartels, J; Christophers, E; Schroder, JM (Feb 23, 2001). "Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.". The Journal of Biological Chemistry. 276 (8): 5707–13. doi:10.1074/jbc.M008557200. PMID 11085990.
  24. ↑ "Press release: PolyMedix". Business Wire
  25. ↑ "PMX-30063 The First And Only Defensin Mimetic Systemic Antibiotic Drug In Human Clinical Trials". 2008.
  26. ↑ "Clinical Trial NCT02324335".Clinicaltrials.gov
  27. ↑ "Brilacidin-OM page".Cellceutix
  28. ↑ "Candidiasis".Cellceutix
  29. ↑ "A Novel Therapeutic For Invasive Candiasis".Fox Chase Chemical Diversity Center
  30. ↑ Lisa K. Ryan; Katie . Freeman; Jorge A Masso-Silva; Klaudia Falkovsky; Ashwag Aloyouny; Kenneth Markowitz; Amy G. Hise; Richard W. Scott; Gill Diamond (July 2014). "Activity of potent and selective host defense peptide mimetics in mouse models of oral candidiasis" (PDF). Antimicrobial Agents and Chemotherapy. 58 (7): 3820–7. doi:10.1128/AAC.02649-13. PMC 4068575Freely accessible. PMID 24752272.
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