Alpha defensin

Alpha defensins are a family of mammalian defensin peptides.

Mammalian defensin
Structure of defensin HNP-3.[1]
Identifiers
SymbolDefensin_1
PfamPF00323
InterProIPR006081
PROSITEPDOC00242
SCOPe1dfn / SUPFAM
TCDB1.C.19
OPM superfamily54
OPM protein1tv0

Defensins are 2-6 kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses,[2] containing three pairs of intramolecular disulfide bonds. On the basis of their size and pattern of disulfide bonding, mammalian defensins are classified into alpha, beta and theta categories. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine.

Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called cryptdins when first discovered.

Human defensins

Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides.[3] Human neutrophil peptides are also known as α-defensins.

Sequences of major human α-defensins:[4]

GeneAliasesPeptideSequence
DEFA1HNP1human neutrophil peptide 1ACYCRIPACIAGERRYGTCIYQGRLWAFCC
HNP2human neutrophil peptide 2  CYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA3HNP3human neutrophil peptide 3DCYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA4HNP4human neutrophil peptide 4VCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRV
DEFA5HD5human defensin 5ATCYCRHGRCATRESLSGVCEISGRLYRLCCR
DEFA6HD6human defensin 6AFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL

HNP-1, HNP-2 and HNP-3 are encoded by two genes DEFA1 and DEFA3 localized at chromosome 8, location 8p23.1. DEFA1 and DEFA3 encode identical peptides except the conversion of the first amino acid from alanine in HNP-1 to aspartic acid in HNP-3; HNP-2 is an N-terminally truncated iso-form lacking the first amino acid. Human neutrophil peptides are found in human atherosclerotic arteries, inhibit LDL metabolism and fibrinolysis and promote Lp(a) binding.[5]

Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.

Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection.[6] 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.[7]

The Virtual Colony Count antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same microplate.[8]

Alpha defensins in human plasma

HNPs have been extensively studied as plasma marker of a range of diseases such as atherosclerosis, rheumatic diseases,[9] infections,[10] cancer,[11] preeclampsia,[12] and schizophrenia.[13] Antibodies directed against fully processed HNP-1 seem to have low affinity for the propeptides, proHNPs. A recent study used antibodies directed against proHNPs to show that the predominant forms of alpha-defensins in plasma are in fact proHNPs.[14] ProHNPs are exclusively synthesized by neutrophil precursors in the bone marrow and appear to be very specific markers of granulopoiesis.

See also

References
  1. Hill CP, Yee J, Selsted ME, Eisenberg D (March 1991). "Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization". Science. 251 (5000): 1481–5. Bibcode:1991Sci...251.1481H. doi:10.1126/science.2006422. PMID 2006422.
  2. Selsted ME, White SH, Wimley WC (1995). "Structure, function, and membrane integration of defensins". Curr. Opin. Struct. Biol. 5 (4): 521–527. doi:10.1016/0959-440X(95)80038-7. PMID 8528769.
  3. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI (Oct 1985). "Defensins. Natural peptide antibiotics of human neutrophils". J Clin Invest. 76 (4): 1427–35. doi:10.1172/JCI112120. PMC 424093. PMID 2997278.
  4. Bowdish DM, Davidson DJ, Hancock RE (2006). "Immunomodulatory Properties of Defensins and Cathelicidins". CTMI. Current Topics in Microbiology and Immunology. 306: 27–66. doi:10.1007/3-540-29916-5_2. ISBN 978-3-540-29915-8. PMID 16909917.
  5. Nassar H, Lavi E, Akkawi S, Bdeir K, Heyman SN, Raghunath PN, Tomaszewski J, Higazi AA (Oct 2007). "alpha-Defensin: link between inflammation and atherosclerosis". Atherosclerosis. 194 (2): 452–7. doi:10.1016/j.atherosclerosis.2006.08.046. PMID 16989837.
  6. V. S. Priyadharshini, F. Ramírez-Jiménez, M. Molina-Macip, et al., “Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection,” Canadian Respiratory Journal, vol. 2018, Article ID 1038593, 6 pages, 2018. https://doi.org/10.1155/2018/1038593.
  7. 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.
  8. Ericksen B, Wu Z, Lu W, Lehrer RI (2005). "Antibacterial Activity and Specificity of the Six Human α-Defensins". Antimicrob. Agents Chemother. 49 (1): 269–75. doi:10.1128/AAC.49.1.269-275.2005. PMC 538877. PMID 15616305.
  9. Vordenbäumen, S; Sander, O; Bleck, E; Schneider, M; Fischer-Betz, R (May–Jun 2012). "Cardiovascular disease and serum defensin levels in systemic lupus erythematosus". Clinical and Experimental Rheumatology. 30 (3): 364–70. PMID 22510487.
  10. Panyutich, AV; Panyutich, EA; Krapivin, VA; Baturevich, EA; Ganz, T (August 1993). "Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis". The Journal of Laboratory and Clinical Medicine. 122 (2): 202–7. PMID 8340706.
  11. Droin, N; Hendra, JB; Ducoroy, P; Solary, E (Aug 20, 2009). "Human defensins as cancer biomarkers and antitumour molecules". Journal of Proteomics. 72 (6): 918–27. doi:10.1016/j.jprot.2009.01.002. PMID 19186224.
  12. Prieto, JA; Panyutich, AV; Heine, RP (January 1997). "Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients?". The Journal of Reproductive Medicine. 42 (1): 29–32. PMID 9018642.
  13. Craddock, RM; Huang, JT; Jackson, E; Harris, N; Torrey, EF; Herberth, M; Bahn, S (July 2008). "Increased alpha-defensins as a blood marker for schizophrenia susceptibility". Molecular & Cellular Proteomics. 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140.
  14. Glenthøj, A; Glenthøj, AJ; Borregaard, N (August 2013). "ProHNPs are the principal α-defensins of human plasma". European Journal of Clinical Investigation. 43 (8): 836–43. doi:10.1111/eci.12114. PMID 23718714.
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