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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000005
MYELOID BIOLOGY: Edited by David C. Dale

Defensins in innate immunity

Zhao, Lea; Lu, Wuyuanb

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Author Information

aFirst Affiliated Hospital, Xi’an Jiaotong University School of Medicine, China

bInstitute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, USA

Correspondence to Wuyuan Lu, Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Maryland, USA. Tel: +1 410 706 4980; e-mail: wlu@ihv.umaryland.edu

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Abstract

Purpose of review

Defensins are a major family of antimicrobial peptides expressed predominantly in neutrophils and epithelial cells, and play important roles in innate immune defense against infectious pathogens. Their biological functions in and beyond innate immunity, structure and activity relationships, mechanisms of action, and therapeutic potential continue to be interesting research topics. This review examines recent progress in our understanding of alpha and theta-defensins – the two structural classes composed of members of myeloid origin.

Recent findings

A novel mode of antibacterial action is described for human enteric alpha-defensin 6, which forms structured nanonets to entrap bacterial pathogens and protect against bacterial invasion of the intestinal epithelium. The functional multiplicity and mechanistic complexity of defensins under different experimental conditions contribute to a debate over the role of enteric alpha-defensins in mucosal immunity against HIV-1 infection. Contrary to common belief, hydrophobicity rather than cationicity plays a dominant functional role in the action of human alpha-defensins; hydrophobicity-mediated high-order assembly endows human alpha-defensins with an extraordinary ability to acquire structural diversity and functional versatility. Growing evidence suggests that theta-defensins offer the best opportunity for therapeutic development as a novel class of broadly active anti-infective and anti-inflammatory agents.

Summary

Defensins are the ‘Swiss army knife’ in innate immunity against microbial pathogens. Their modes of action are often reminiscent of the story of ‘The Blind Men and the Elephant’. The functional diversity and mechanistic complexity, as well as therapeutic potential of defensins, will continue to attract attention to this important family of antimicrobial peptides.

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INTRODUCTION

Defensins are a family of 2–5-kDa, disulfide-knotted, and functionally multifaceted antimicrobial peptides that play important roles in innate immune defense against microbial infection. On the basis of disulfide topology, defensins are classified into three structural families: alpha, beta, and theta. In humans, there exist only alpha and beta-defensins. To date, six human alpha-defensins have been identified, including human neutrophil defensins 1–4, known as human neutrophil peptides or HNPs 1–4, and human enteric defensins 5–6 or HD5 and HD6. Lehrer and Lu [1▪] have given an extensive recent review on human alpha-defensins in innate immunity. More than 30 beta-defensin genes are believed to exist in human epithelia, only a few of which, however, have been characterized thus far at the protein level. A recent review on human beta-defensins, given by Semple and Dorin [2], focuses on their immunomodulatory properties, as well as roles in fertility [3], development, wound healing, and cancer. Weinberg et al.[4] have also given a thorough examination of beta-defensins that play both advantageous and detrimental roles in health and disease. Theta-defensins, expressed in the leukocytes and bone marrow of certain nonhuman primates, are a structurally unique class of macrocyclic peptides of 18-amino acid residues with a ladder pattern of three disulfides. To date, 6 theta-defensins from rhesus macaques and 10 theta-defensin isoforms from olive baboons have been identified; a series of putative hominid homologs of rhesus macaque theta-defensins encoded by human pseudogenes, termed retrocyclins, have been extensively studied. Theta-defensins are a topic covered by Lehrer et al.[5▪] in their very recent review. This review summarizes important progress made during the past year in the field of defensin research, with a focus on alpha and theta-defensins in innate immunity as most members of the two structural classes of defensins are of myeloid origin.

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DEFENSINS DO NOT FUNCTION BY JUST POKING HOLES IN THE BACTERIAL MEMBRANE!

Like many other amphipathic antimicrobial peptides, defensins are composed of both cationic and hydrophobic residues, capable of interacting with and potentially disintegrating negatively charged bacterial membranes. Membrane disruption had long been thought to be the prevailing mechanism of killing of bacteria by defensins. Whereas this mode of action may well be true with Gram-negative strains of bacteria, multiple defensins have recently been shown to kill Gram-positive strains of bacteria such as Staphylococcus aureus by sequestering the bacterial cell wall precursor lipid II and inhibiting bacterial cell wall synthesis [6,7]. Thus, defensins can act against bacteria through multi-pronged attacks on cellular targets not limited to ‘the usual suspect’. An interesting recent finding further reveals that HNP1 at sublethal concentrations interacts with the ExPortal – a unique microdomain of the cellular membrane through which the Gram-positive pathogen Streptococcus pyogenes secretes proteins [8▪]. This interaction disrupts ExPortal function and interferes with S. pyogenes infection and survival by blocking ExPortal-mediated secretion of certain bacterial toxins.

Chu et al. have made a paradigm-shifting discovery with respect to the mechanisms of action of the enteric alpha-defensin HD6 in mucosal innate immunity [9▪▪]. Both HD5 and HD6 are highly expressed by secretory Paneth cells of the small intestine – highly specialized epithelial cells that play critical roles in intestinal homeostasis and innate immune defense against enteric pathogens [10▪,11▪,12]. Defects in Paneth cells and reduced expression of the enteric alpha-defensins are linked to ileal Crohn's disease – a chronic inflammatory disorder of the small intestine [10▪,13,14]. However, unlike its close ‘cousin’ HD5 and other human alpha-defensins, HD6 shows little bactericidal and membranolytic activity in vitro. Yet, HD6 fully protects against bacterial invasion in HD6+/− transgenic mice challenged with the enteric pathogen Salmonella typhimurium. Extensive biochemical, biophysical, and structural studies reveal that HD6 self-assembles, upon binding to bacterial surface proteins, into structured nanonets, entangling S. typhimurium in vitro and in vivo. The unique ability of HD6 to entrap bacteria, instead of killing them directly, is ascribed to its acute tendency to form elongated, high-order oligomers, different significantly from the known structures of other human alpha-defensins. In fact, electrostatic interactions between His27 of one monomer and the C-terminal residue Leu32 of another have been shown to be critical for stabilizing functional HD6 nanonets. These important findings underscore the mechanistic complexity and multiplicity of defensins in innate immune defense against bacterial pathogens.

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A NEW TWIST IN THE OLD STORY: HIV-1 AND DEFENSINS

Despite the fact that the anti-HIV-1 activity of HNPs is well documented in the literature, early studies of their inhibition of HIV-1 replication were not without controversy. It is now generally accepted that defensin inhibition of HIV-1 infection in vitro is mechanistically complex and diverse, involving several viral components and enabling host factors [15]. A recent study by Demirkhanyan et al.[16▪] further demonstrated that HNP1 inhibits multiple steps of HIV-1 entry and fusion by interfering with gp120 binding to CD4 and coreceptors, formation of the fusogenic 6-helix bundle structure of gp41, and selective uptake of the virus. Interestingly, in light of known lectin-like properties of HNP1, the presence of serum, although greatly reducing the inhibitory activity of HNP1, does not attenuate its ability to bind cellular and viral proteins. The authors suggest that this somewhat unexpected discordance between the defensin binding and inhibitory activity may be indicative of serum-sensitive oligomeric forms of HNP1 responsible for its antiviral effect through cross-linking virus and host glycoproteins. In a subsequent study, the same group reports that sub-inhibitory concentrations of HNP1 in the presence of serum potentiate neutralizing antibodies against the first heptad repeat domain of HIV-1 gp41 by prolonging the exposure of the viral protein on the cell surface [17].

A recent controversy over HIV-1 and defensins arises from in-vitro studies of the two enteric alpha-defensins HD5 and HD6. Klotman et al. [18] and Rapista et al. [19] previously reported that preincubation of serum-free HIV-1 with HD5 or HD6 substantially promoted subsequent infection of primary CD4+ T cells (in the presence of serum) in a CD4 and coreceptor-independent manner. The enhancing effect of the enteric alpha-defensins on HIV-1 infection was ascribed to their ability to promote HIV attachment to target cells [19]. Since Neisseria gonorrhoeae infection of cervico-vaginal tissues induced HD5 and HD6 expression [18], their findings may partially explain that sexually transmitted infections facilitate HIV transmission in vivo[20]. Furci et al.[21] recently showed, however, that under serum-free and low-ionic-strength conditions (mimicking mucosal fluids), HD5 inhibits HIV-1 infection of primary CD4+ T cells through interference with gp120–CD4 interactions, and down-regulation of the coreceptor CXCR4. The contradictory in-vitro data reported by the two laboratories appear, at least in part, due to the different experimental parameters used. Lu and de Leeuw [22] demonstrate that in the absence of serum, HD5 is capable of inducing dose-dependent apoptosis of intestinal epithelial cells and primary CD4+ T cells. Ding et al.[23] have also made similar observations on the pro-apoptotic property of HD5 with primary CD4+ T cells in a serum-free medium. Thus, it remains a distinct possibility that HD5-induced cell death could be functionally associated, at least in part, with the apparent HD5 inhibition of HIV-1 infection under serum-free and low-ionic-strength conditions [21]. Obviously, more study is needed to reconcile the conflicting data in order to establish a potential role of HD5 in mucosal immunity against HIV-1 infection in vivo.

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STRUCTURAL BASIS OF FUNCTIONAL MULTIPLICITY OF DEFENSINS

Growing evidence suggests that the interplay between cationicity and hydrophobicity, as well as the ability to dimerize, oligomerize, and multimerize on target molecules of bacterial, viral, and host origin, attribute to functional versatility of defensins [1▪]. All human alpha-defensins, with the notable exception of HD6, form a canonical dimer on their own [24], which may further self-associate to form oligomers [25]. By using a chemical protein engineering approach to preparing an obligate monomer and a constitutive dimer of HNP1, which were structurally verified by X-ray crystallography, Pazgier et al.[26▪] dissected the functional importance of dimerization of HNP1. An impaired ability of HNP1 to dimerize correlated with its reduced antibacterial activity against S. aureus, inhibition of anthrax lethal factor, and binding to HIV-1 gp120. Not surprisingly, several hydrophobic residues, and Trp26 at the dimer interface in particular [27], were found to be essential for mediating HNP1 dimerization and oligomerization, and functionally important. Similar findings were made with the enteric alpha-defensin HD5 [28], where Leu29 at the dimer interface, equivalent to Trp26 of HNP1, was identified to play a dominant structural and functional role. Of note, dimerization of HNP1 or HD5 was inconsequential with respect to its antibacterial activity against Escherichia coli[26▪,28], indicative of different mechanisms of action of alpha-defensins in the killing of Gram-positive and Gram-negative strains [1▪].

The functional importance of hydrophobicity as well as quaternary structure of alpha-defensins is also evident in their action against pathogenic viruses. HNPs and HD5 were previously reported to inhibit human papillomavirus (HPV) infection by blocking virion escape from endocytic vesicles [29]. HD5 blocks human adenovirus (AdV) infection by binding and stabilizing viral capsid proteins, thus preventing capsid disassembly and uncoating required for infectivity [30,31]. Recent mutational studies of HD5 indicate that Leu29 is critical for antiviral activity against both HPV and AdV, and that hydrophobicity of residues at position 29 directly correlates with capsid binding and antiviral activity [32▪]. Importantly, an obligate monomer of HD5 shows greatly attenuated antiviral activity despite its ability to productively bind the AdV capsid, demonstrating the functional importance of HD5 quaternary structure [32▪].

Of note, although selective Arg residues of HD5 were also found to contribute to antiviral activity, charge-neutral substitutions of lysine for these Arg residues abrogated HD5 inhibition, suggesting that Arg-mediated HD5 interactions with AdV and HPV capsids were not purely cationicity-dependent [32▪]. Human alpha-defensins carry a significantly fewer number of cationic residues than their counterparts in the beta-defensin family, and, unlike beta-defensins, Arg is strongly selected over Lys in their sequences. Complete substitutions of Arg with Lys, although attenuating antibacterial activity of the mouse alpha-defensin cryptidin-4, do not affect rhesus myeloid alpha-defensin 4 [33]. The apparent functional advantage of Arg over Lys in HD5 may reflect the stronger ability of Arg to engage in extensive electrostatic interactions with AdV and HPV capsids via salt bridges, H-bonds, and cationic–aromatic or cationic contacts. Position-dependent enhancement in cationicity of alpha-defensins in the form of Arg improves antiviral activity of HD5 against HSV-2 [34]. Nevertheless, hydrophobicity and quaternary structure likely play a more prominent functional role [1▪].

Theta-defensins also self-associate in aqueous solution – a property thought to be relevant to their mechanism of action [35]. Interestingly, whereas the cyclic cysteine ladder in theta-defensins is important for their structure and thermal/proteolytic stability, their antibacterial and membrane-binding activities are dependent on the cyclic backbone rather than disulfide bonding [36]. These findings are in contrast with human alpha-defensins, whose tertiary structure afforded by three disulfide bonds is generally required for most biological functions, including antibacterial activity against S. aureus[1▪]. However, disulfide binding in human alpha-defensins is largely dispensable for the killing of E. coli, suggesting, again, that they kill Gram-positive and Gram-negative bacteria in a different manner.

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THETA-DEFENSINS AS PROMISING THERAPEUTIC AGENTS

Defensins directly kill different strains of bacteria, inhibit infection of cells by various enveloped and nonenveloped viruses, and neutralize many secreted bacterial toxins; thus they are ideally suited for therapeutic development as a novel class of broadly active anti-infective agents. Recently, Liu et al. [37▪] and Teles et al. [38] have discovered that induction of endogenous antimicrobial response via gene regulation can be a potential therapeutic strategy for the treatment of leprosy and other chronic infectious diseases where cellular immune responses are dysregulated. Particularly attractive as potential therapeutic compounds are theta-defensins, originally discovered by Tang et al.[39]. In addition to their antibacterial properties, theta-defensins and their analogs are highly active against a battery of infectious viral pathogens [5▪], including herpes simplex viruses, influenza A virus [40], SARS coronavirus, HIV-1, and dengue virus [41]. Theta-defensins are also able to protect mice in vivo from infection by highly pathogenic spores of the anthrax bacillus. More recently, Schaal et al.[42▪] have demonstrated that rhesus macaque theta-defensins are potently anti-inflammatory by inhibiting the release of pro-inflammatory cytokines in vitro and in vivo, promising a novel class of therapeutics for the treatment of bacteremic sepsis and possibly autoimmune diseases. Extensive preclinical studies are ongoing aimed at developing retrocyclins as new antiviral agents to prevent sexually transmitted infections caused by HIV-1 [43–45]. Importantly, theta-defensins have been shown to be nontoxic in culture and animal models, well tolerated in primary tissues, nonimmunogenic in adult chimpanzees, and highly stable in vivo[42▪,46].

An economical and efficient production of theta-defensins is essential for the success of their therapeutic development. In an elegant study using aminoglycosides to read-through the premature termination codon harbored in human theta-defensin genes, Venkataraman et al.[47] recently achieved expression of human theta-defensins in epithelial cells and cervico-vaginal tissues. The more commonly used protocol for the production of theta-defensins is chemical synthesis, typically involving inefficient oxidative folding and head-to-tail backbone cyclization, as well as multiple steps of HPLC purification. Recent advances in synthetic peptide chemistry and the development of native chemical ligation (NCL) in particular have made it possible to chemically synthesize large quantities of theta-defensins [48▪]. The state-of-the-art NCL technique was originally developed by Dawson and Kent [49], and Dawson et al.[50] to allow two fully unprotected synthetic peptides to react chemoselectively in aqueous solution, resulting in a longer polypeptide chain linked by a new peptide bond. The ligation reaction requires the presence of a C-terminal alpha-thioester moiety on the upstream peptide and an N-terminal cysteine residue on the downstream peptide. However, when both an N-terminal Cys and a C-terminal alpha-thioester moiety are present on the same peptide, a fast intra-molecular ligation reaction, that is, end-to-tail backbone cyclization, takes place nearly quantitatively. This highly efficient methodology has been successfully used for the synthesis of many cyclic proteins and peptides, including theta-defensins [36,51▪]. Of note, Muir [52] pioneered a technique termed ‘expressed protein ligation’ that utilizes an intein-based expression system to generate recombinant thioester-bearing peptides and proteins, which can be captured by or ligated with another Cys-containing peptide. This technique has greatly expanded the application of ‘native chemical ligation’ to the synthesis of novel protein molecules including cyclic proteins and peptides. Recombinant production of theta-defensins using the intra-molecular version of ‘expressed protein ligation’ has recently been achieved in a bacterial expression system [53▪]. Interestingly, Rapireddy et al.[54] have recently reported the engineering of a functional theta-defensin containing noncovalent Watson–Crick hydrogen bonds in place of three disulfide bridges, eliminating the possibility of non-native disulfide parings in theta-defensins associated with their oxidative folding.

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ALPHA-DEFENSIN PROCESSING AND MATURATION

Human alpha-defensins are produced in vivo as pro-forms and proteolytic processing to removal the N-terminal prodomain is required for functional activation. Whereas neutrophil alpha-defensins reside in azurophil granules as mature and active forms, they exist abundantly in the bone marrow plasma predominantly as secreted pro-HNPs [55]. A recent study by Tongaonkar et al.[56] identified neutrophil elastase and proteinase 3 but not cathepsin G that colocalize with HNPs in azurophil granules as pro-HNP1-activating convertases.

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CONCLUSION

The tertiary structures of alpha-defensins, characterized by three antiparallel beta-strands stabilized by three intra-molecular disulfide bridges, are well conserved. However, high variability at both the primary and quaternary structural levels renders alpha-defensins extremely versatile functionally. Even within the alpha-defensin family, human proteins behave differently in many aspects from their mouse counterparts – cryptidins [57,58], for example. Functional diversity coupled with mechanistic complexity as well as therapeutic potential of defensins warrant continued studies of these fascinating molecules to gain a better understanding of their modes of action, albeit controversial and debatable at times, in the great variety of biological processes. We envisage with optimism clinical trials in the future for theta-defensins as a novel class of broadly active anti-infective and anti-inflammatory agents.

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Acknowledgements

W.L. has been supported by NIH grants for the past 10 years and L.Z. is a Guanghua Scholar supported by Xi’an Jiaotong University School of Medicine.

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Conflicts of interest

There are no conflicts of interest.

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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

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REFERENCES

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This is a comprehensive review of alpha-defensins by Robert Lehrer who discovered this class of antimicrobial peptides first from the rabbit and later from humans, and who coined the term ‘defensin’.


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This interesting study describes a systematic mutational study of HD5 with respect to its capsid-binding and antiviral activity against human adenovirus.


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Keywords

antimicrobial peptides; defensins; innate immunity

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