Distinct Defensin Profiles inNeisseria gonorrhoeaeandChlamydia trachomatisUrethritis Reveal Novel Epithelial Cell-Neutrophil Interactions

Abstract

Defensins are key participants in mucosal innate defense. The varied antimicrobial activity and differential distribution of defensins at mucosal sites indicate that peptide repertoires are tailored to site-specific innate defense requirements. Nonetheless, few studies have investigated changes in peptide profiles and function after in vivo pathogen challenge. Here, we determined defensin profiles in urethral secretions of healthy men and men with Chlamydia trachomatis-and Neisseria gonorrhoeae-mediated urethritis by immunoblotting for the epithelial defensins HBD1, HBD2, and HD5 and the neutrophil defensins HNP1 to -3 (HNP1-3). HBD1 was not detectable in secretions, and HBD2 was only induced in a small proportion of the urethritis patients; however, HD5 and HNP1-3 were increased in C. trachomatis infection and significantly elevated in N. gonorrhoeae infection. When HNP1-3 levels were low, HD5 appeared mostly as the propeptide; however, when HNP1-3 levels were >10 g/ml, HD5 was proteolytically processed, suggesting neutrophil proteases might contribute to HD5 processing. HD5 and HNP1-3 were bactericidal against C. trachomatis and N. gonorrhoeae, but HD5 activity was dependent upon N-terminal processing of the peptide. In vitro proteolysis of proHD5 by neutrophil proteases and analysis of urethral secretions by surface-enhanced laser desorption ionization substantiated that neutrophils contribute the key convertases for proHD5 in the urethra during these infections. This contrasts with the small intestine, where Paneth cells secrete both proHD5 and its processing enzyme, trypsin. In conclusion, we describe a unique defensin expression repertoire in response to inflammatory sexually transmitted infections and a novel host defense mechanism wherein epithelial cells collaborate with neutrophils to establish an antimicrobial barrier during infection.

Effect of Corticosteroids and Neuropeptides on the Expression of Defensins in Bovine Tracheal Epithelial Cells

“…Conversely, Duits et al reported no effect of dexamethasone on hBD-1 or hBD-2 expression, whereas basal and induced hBD-3 mRNA expression was inhibited by dexamethasone in primary bronchial epithelial cells (16). Reasons for this discrepancy are not clear, but considering our finding that dexamethasone did not significantly affect the LPS-induced upregulation of LAP, it seems likely that expression of each ␤-defensin is regulated somewhat independently, as has been shown for their pathogen-specific induction in humans (34).…”

Human α-defensins block papillomavirus infection

“…In Paneth cells, this processing is accomplished by tryptic digestion during or just after secretion into the intestinal lumen (55). A recent report has shown that, in the male urethra, HD-5 processing may depend on proteases secreted by neutrophils (50). Whether alternative HD-5 isoforms, other than the dominant tryptic form we have studied here, are active against papillomaviruses remains to be determined.…”

“…One report observed HD-5 peptide at various sites in the human female genital tract and found high ng͞ml levels of HD-5 in vaginal wash material (48). Other studies have reported HD-5 expression in the testes and male urethra, as well as in breast milk and keratinocytes of the oral and airway mucosa (49)(50)(51)(52)(53). In some of these studies, HD-5 expression appeared to correlate with local inflammation.…”

“…The ability of ␣-defensins to substantially inhibit in vitro HPV infection, even 6 h after cell-surface binding, implies that they might be effective as a postcoital microbicide. Because ␣-defensins have been found to inhibit HIV-1, herpes simplex viruses, Neisseria gonorrhoeae, and Chlamydia trachomatis, they could potentially function as broad-spectrum topical microbicides to simultaneously block multiple sexually transmitted pathogens (37,50,61,62). Prevention of the sexual transmission of HPV might be a particularly useful endpoint for preliminary efficacy trials of broad-spectrum topical microbicides.…”

Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

“…[11][12][13] These antimicrobial polypeptides, some of which are induced in response to PAMP exposure, are effective at inhibiting Gram-positive and Gram-negative bacteria, fungi, and enveloped viruses, including Neisseria gonorrhoeae, Chlamydia trachomatis, Candida albicans, Herpes Simplex Virus-2, and Human Immunodeficiency Virus-1. [14][15][16][17][18][19][20][21][22][23] It is well known that estrogens, which act throughout the body, have both anti-inflammatory and proinflammatory functions. For example, E 2 enhances the production of proinflammatory interferon-γ and anti-inflammatory IL-10 in T cells.…”