Current Opinion in Hematology:
Multispecific myeloid defensins
Lehrer, Robert I
David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Correspondence to Robert I. Lehrer, Professor of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA Tel: +1 310 825 5340; Fax: +1 310 206 8766; e-mail: email@example.com
Disclosures: The author affirms that any opinions expressed in this review are his own, that no conflict of interest exists, and that his own research has been funded exclusively by government grants for the past decade.
Purpose of review: This review describes recent progress in our understanding of defensins and their contributions to innate immunity. Defensins are small, cysteine-rich endogenous antibiotic peptides. Human neutrophils contain large amounts of three α-defensins (HNP-1–HNP-3), and smaller amounts of a fourth, HNP-4. Monocytes and macrophages generally lack defensins, but they release messengers that induce the synthesis of β-defensins in epithelial cells.
Recent findings: In addition to their antimicrobial and immunomodulatory effects, HNP-1–HNP-3 possess antiviral and toxin-neutralizing properties. Induction of β-defensins in epithelial cells is mediated by cell-surface Toll-like receptors or cytoplasmic peptidoglycan receptors that can recognize pathogen-associated molecules. Mutations in Nod2, a cytoplasmic peptidoglycan receptor, are associated with reduced levels of intestinal α-defensins and ileal Crohn's disease. Human defensin genes show marked copy-number polymorphism. High level constitutive expression of defensins may afford protection against HIV-1 and other defensin-sensitive pathogens. Theta-defensins (cyclic octadecapeptides found in nonhuman primates) have impressive antiviral and antitoxic properties.
Summary: The multiple properties of defensins contribute to human innate immunity against bacteria, bacterial toxins, and viruses.
Abbreviations HNP: human neutrophil peptide; PMN: polymorphonuclear cell.
Defensins are endogenous peptide antibiotics produced by certain leukocytes and many epithelial cells. Their antimicrobial, toxin-neutralizing, antiviral and immunomodulatory properties augment innate resistance to infection. Some defensins attract monocytes  and immature dendritic cells , and are immunoadjuvants [3•,4]. Others may accelerate wound repair [5,6]. Humans express two subfamilies of defensin peptides: α and β-defensins. Rhesus macaques express an additional subfamily, θ-defensins, found only in nonhuman primates . Other recent reviews of defensins are available [3•,7,8••,9,10•,11••].
We can briefly summarize the first billion years of defensin history as follows. Plants [12,13•], fungi [14••] and various invertebrates  contain cysteine-rich antimicrobial peptides that are also called defensins. Plectasin, a recently described fungal defensin, shows high sequence homology to defensin peptides of dragonflies and other primitive insects [14••], consistent with descent from a common precursor. If this interpretation is correct, ancestral defensin genes existed before the fungal and insect lineages diverged (i.e., over a billion years ago). Alpha and β-defensins evolved from a common ancestral gene  and θ-defensin genes are modified α-defensin genes . Alpha-defensins exist only in primates and glires (rodents and rabbits), relative latecomers to the planet. Beta-defensins exist in birds [18,19], reptiles [20,21] and bony fish . Alpha/β/θ-defensins and plant/fungal/insect defensins share many structural features and activities. Peptides resembling β-defensins exist in horseshoe crabs  and sea anemones , but their relationship to the aforementioned defensins is uncertain.
Cysteine-rich antimicrobial peptides were noted in rabbit neutrophils (polymorphonuclear cells; PMNs) over 40 years ago [25,26]. Their human homologues were described 20 years later . Neutrophils of cattle and chickens contain multiple β-defensins and no α-defensins. Neutrophils of mice, sheep and pigs lack defensins completely, but contain one or more cathelicidin peptides [28••]. Humans lost their ability to produce θ-defensin peptides as the result of a mutation that occurred approximately 7.5 million years ago .
Alpha, β and θ-defensins possess three intramolecular cystine disulfide bonds and have largely β-sheet structures. Beyond those shared features, defensin peptides have quite variable sequences. When recently duplicated mammalian defensin genes were examined, nonsynonymous (amino-acid-altering) substitutions exceeded synonymous substitutions in the mature defensin region . Of the 29–35 amino acid residues in an α-defensin molecule, only nine are highly conserved between species: six cysteines, one glycine, one arginine and one glutamic acid. The arginine and glutamic acid residues form a salt bridge  that enhances resistance to degradation by neutrophil elastase . A recent study  compared correctly folded hBD-3 (i.e., with its cysteines paired in a 1: 5, 2: 4, 3: 6 pattern) with aberrantly folded hBD-3 variants. The peptides differed in their chemotactic activity for monocytes but exerted similar antimicrobial activity against Escherichia coli. The authors concluded that disulfide bond pairing in hBD-3 was fully dispensable for its antimicrobial function. Another study , involving additional organisms and different assay conditions, reached a similar conclusion. Because the net charge of hBD-3 (+11) greatly exceeds that of other human defensins the dispensability of disulfide bonds for antimicrobial activity may not apply to the other defensins family members.
A recent study concluded that membrane depolarization contributed to the rapid killing of many bacteria by human defensins, and that additional activities, such as activation of cell-wall lytic enzymes, affected organisms such as staphylococci [10•]. Indirect actions of defensins influenced outcome when newborn piglets were challenged with Bordetella pertussis, the whooping cough organism. Piglets receiving intrapulmonary porcine β-defensin-2 were protected, even though the peptide lacked in-vitro activity against B. pertussis .
Human neutrophil peptides (HNPs) 1–3 were reported to inactivate herpes simplex, cytomegalovirus, influenza A, and vesicular stomatitis virus over 20 years ago  and were reported to inactivate HIV-1 in 1993 . These reports received little attention until HNPs 1–3 were linked to a soluble and noncytotoxic anti-HIV-1 principle called ‘CAF’, supposedly secreted by the CD8(+) T-lymphocytes of untreated, clinically stable HIV-1-infected individuals . After considerable controversy [38,39], the HNP/CAF identity was recanted. This was not because HNPs 1–3 lacked anti-HIV-1 activity, or because the cultured CD8(+) T-cells did not contain HNPs 1–3. Instead, the reinterpretation resulted from the observation that HNPs 1–3 found in the T-lymphocytes of these individuals were synthesized by other cells in the feeder layers. Which cells had contributed their defensins in these in-vitro experiments was not determined. Others have shown that natural killer cells and γδ-T-cells synthesize HNPs 1–3 , and that HNPs 1–3 inactivate extracellular HIV-1 virions and inhibit one or more steps subsequent to reverse transcription and viral integration [41•].
HNPs 1–3 have a lectin-like ability to bind viral and cell-surface glycoproteins, including gp120 and CD4 . It is unclear if this property contributes to anti-HIV activity, but it may concentrate HNPs 1–3 at the virus–target cell receptor interface and enable defensins to accompany virions that enter the host cell. Retrocyclins and other θ-defensins are lectins  that inhibit HIV-1 entry [44,45] by binding the second heptad repeat domain (HR2) of gp41 and preventing 6-helix bundle formation [46•].
HNPs and retrocyclins also block infection by type 2 herpes simplex viruses (HSV-2). Retrocyclin-2 prevented HSV-2 attachment, whereas HNPs 1–3 acted at postbinding steps . HNPs 1–3 (and HD-5) protected HeLa cells from papillomaviruses, but human β-defensins hBD-1 and hBD-2 showed little or no activity . Papillomaviruses enter cells via a clathrin-dependent endocytic pathway. Neither HNP-1 nor HD-5 prevented endocytosis of papillomavirus, but both kept the virions from exiting the endocytic vesicles and entering target cells. A similar mechanism allows θ-defensins and HBD-3 to block entry of influenza A virions [49•].
The antiviral activity of α-defensins is not restricted to enveloped viruses, since HNP-1 (and hBD-1) also protects against infection by adenovirus [50,51], which also enters cells by endocytosis in clathrin-coated vesicles . A review of the antiviral properties of defensins that centers on HIV-1 is available [53•].
Certain defensins enhance adaptive immune responses in mice [54,55]. More recently, α-defensins were shown to inactivate several potent bacterial exotoxins, including those released by Bacillus anthracis and Corynebacterium diphtheriae. The lethal toxin of B. anthracis contains two proteins: lethal factor and protective antigen. Lethal factor is a substrate-specific, zinc-metalloprotease that cleaves mitogen-activated protein kinase kinases. Protective antigen enables lethal factor to enter cells, where its enzymatic properties disrupt key transduction pathways. HNPs 1–3 inhibited lethal factor's enzymatic activity noncompetitively, prevented cytotoxicity in murine macrophages treated with lethal toxin, and protected mice from an otherwise fatal dose of this toxin [56••]. Theta-defensins also inactivated lethal factor and protected murine macrophages from toxin-induced cytotoxicity. Micromolar θ-defensin concentrations killed vegetative B. anthracis cells and prevented anthrax spores from germinating .
HNP-1 inhibits diphtheria toxin and exotoxin A of Pseudomonas aeruginosa, Both toxins are members of the mono-ADP-ribosyltransferase enzyme family [58•] that irreversibly inactivate elongation factor-2, an essential host cell protein. HNPs 1–3 also inactivate cholesterol-dependent cytolysins, exotoxins produced by many Gram-positive bacteria (W. Wang, R.I Lehrer, unpublished observation).
Some defensins (e.g., HNPs 1–3 and hBD-1) are expressed constitutively, and others are induced via protein receptors on the cell surface or in the cytoplasm that recognize pathogen-associated molecular patterns. The 10 human cell surface Toll-like receptors (TLRs) include TLR2, which senses peptidoglycan, lipopeptides, and lipoproteins; TLR3, which senses double-stranded viral RNA; TLR4, which senses lipopolysaccharide, and TLR5, which binds bacterial flagellins . TLRs mediate increased defensin expression via pathways that cause nuclear localization of NF-κB and activate mitogen activated protein kinase .
Adults produce approximately 2 × 109 neutrophils/kg body weight/day, and since each 2 × 109 PMNs contains approximately 10 mg of HNPs 1–3, the baseline production of HNPs 1–3 is about 10 mg/kg/day . What happens to these peptides when neutrophils die is unknown. Many neutrophils enter the mouth by traversing gingival crevices, and crevicular fluid contains high concentrations of HNPs 1–3  that may augment periodontal defenses .
Exposing monocytes and lymphocytes to microbe-derived molecules stimulates epidermal expression of hBD-1–hBD-3 by different pathways . hBD-3 expression is governed by the epidermal growth factor receptor, which also enhances hBD-3 expression after sterile wounding .
NOD2 (nucleotide-binding oligomerization domain protein 2) is a cytosolic sensor-protein that recognizes muramyl dipeptide, a building block of bacterial cell walls. Activation of NOD2 by muramyl dipeptide induces hBD-2 expression in human embryonic kidney cells, via a process requiring AP-1 and NF-κB [65•]. Primary keratinocytes express NOD2 and respond to muramyl dipeptide by releasing hBD-2 [65•]. NOD2 is expressed abundantly in human monocytes and intestinal Paneth cells . Many patients with ileal Crohn's disease have a mutated NOD2 gene , and their intestinal Paneth cells show reduced expression of intestinal α-defensins [68•]. NOD2 mutations may predispose to Crohn's disease by failing to sense certain intestinal bacteria, or by failing to link recognition to a response that includes α-defensin expression. Crohn's disease in other sites may be associated with impaired induction of colonic β-defensins, hBD-2 and hBD-3 [65•,69].
Lipopolysaccharide-stimulated human monocytes and uterine macrophages release bioactive IL-1β, which induces hBD-2 synthesis in uterine epithelial cells . Studies with human lung epithelial and macrophage-like cell lines led to similar conclusions . Beta-chemokines (MIP-1α, MIP-1β, and RANTES) cause PMNs to degranulate and release HNPs 1–3 . High levels of these chemokines were found in sera from nine Taiwanese women who remained uninfected despite multiple sexual contacts with HIV-1-infected partners. Their blood contained increased numbers of partially degranulated PMNs that had released their α-defensins . In nine Italian women who remained uninfected despite high-level exposure to HIV-1, constitutive α-defensin production in their peripheral CD8(+) T cells was 10-fold higher than that in healthy, uninfected controls .
Alpha-defensins are highly expressed by human natural killer cells [40,74] and exposing these cells to bacterial antigens [e.g., flagellin and Klebsiella pneumoniae outer membrane protein A (OmpA)] stimulated both defensin synthesis and release .
Many defensin genes cluster within a two-megabase region of human chromosome 8p23.1 whose segmental duplications and anomalies make it difficult to associate disease entities to defensin polymorphisms . Nevertheless, asthma and atopy were reported to be associated with DefB1 polymorphisms [77,78] and two different β-defensin-1 polymorphisms were associated with chronic obstructive pulmonary disease phenotypes in Japanese  and Chinese  populations, but not in a Caucasian population .
Human DEFA1 and DEFA3 genes occur in cassettes of 19 kb tandem repeats that vary from four to 11 per diploid genome. Approximately 10% of people tested lack DEFA3 genes completely, and their neutrophils contain only HNP-1 and HNP-2 [82•]. The β-defensin locus on 8p23 contains genes encoding hBD-1, hBD-2, hBD-3 and hBD-4. Three of these genes are highly polymorphic in European populations . Underlying causes for this complexity were recently reviewed [84••,85]. A genomics approach based on hidden Markov models identified 28 new human β-defensin genes, most of which appeared to be transcribed. These new genes clustered at four loci: 8p22 (11 genes and one pseudogene), 6p12 (five genes), 20q11.1 (10 genes) and 20p13 (five genes) .
Several β-defensin like genes exist in zebrafish and are constitutively expressed in the gills, gonad, gut, kidney, muscle, skin and spleen . Chickens have at least 13 different β-defensin genes, with seven (gallinacins 1–7) expressed in bone marrow and the respiratory tract, and the others primarily in the liver and urogenital tract .
Human α-defensin [82•,87•,88] and β-defensin genes show marked copy number polymorphism. In two studies that examined 138 persons, the combined copy numbers of genes encoding HNP-1 (DEFA1) and HNP-3 (DEFA3) ranged from four to 14 per diploid genome [82•,87•]. The DEFA3 allele was absent in approximately 10% of normal subjects. HNP-2, a 29-residue peptide, is identical to residues two to 30 of both HNP-1 and HNP-3, and is derived from one or both of these by the posttranslational removal of an N-terminal alanine from HNP-1 or an aspartic acid from HNP-3. The genes that encode hBD-3 (DEFB103A) and hBD-4 (DEFB4) varied from two to eight copies per diploid genome. Copy numbers of DEFA1/DEFA3 genes and the DEFB4 and DEFB103A genes varied independently [87•]. It is not known if variability in defensin gene copy numbers influences their abundance in neutrophils, natural killer cells and CD8(+) T-cells, and affects resistance to viral or microbial infection.
These 18-residue defensins, expressed in the neutrophils of nonhuman primates, are the only known circular peptides of animal origin  and the smallest known carbohydrate-binding molecules (lectins) . Human θ-defensin genes exist in multiple copies, and are transcribed [17,44]. The human θ-defensin genes, however, and their mRNA contain a premature stop codon mutation in the signal sequence. Retrocyclins are synthetic θ-defensin peptides based on sequences encoded in these human pseudogenes. In-vitro, retrocyclins prevented HIV-1 [44,46•], influenza A [49•] and herpes simplex viruses  from entering cells. Retrocyclins also killed B. anthracis, inactivated its lethal toxin, and prevented anthrax spores from germinating . While many of these activities resembled those of α-defensins, the mechanisms differed in many details.
The principal myeloid α-defensins, HNPs 1–3, are expressed in largest amount in neutrophils. Consequently, neutropenia is the most commonly encountered setting associated with myeloid defensin deficiency. Since neutrophils possess and use many other antimicrobial weapons, it is difficult to assess the overall significance of defensins to their function. Synthesis of HNPs 1–3 by human natural killer cells [75,90] and CD8(+) T cells is established, but whether their ability to produce these defensins is influenced by the gene copy number polymorphism described above is uncertain. It would be worth measuring defensin gene copy numbers in individuals who appear unusually resistant to infection by defensin-sensitive viral and microbial pathogens.
Defensins are central components of the human innate immune system. Although their antimicrobial activities are well documented, their antitoxic and antiviral properties are just beginning to attract attention. The marked copy number polymorphism of human defensin genesis is intriguing, especially if it can ultimately help to explain why some people may be more resistant to infections than others, perhaps including HIV-1, that are caused by defensin-susceptible pathogens.
I thank the NIH for its past support of my research. I also thank those currently working to decipher the many remaining mysteries of defensins.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 64–65).
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