Identification and Characterization of a Mucosal Antimicrobial Peptide Expressed by the Chinchilla (Chinchilla lanigera) Airway

Harris, Randall H.; Wilk, Dennis; Bevins, Charles L.; Munson, Robert S.

doi:10.1074/jbc.m400499200

Cited by 23 publications

(38 citation statements)

References 34 publications

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“…More importantly, synthetic cBD was more effective in killing C. albicans isolated from vaginal epithelium than one isolated from hematogenous origin, strongly suggesting that cBD plays an essential role as an epithelium-derived antibiotic that functions as an immediate line of defense against genital pathogens. The MIC for cBD for C. albicans is in agreement with previous reports (7,23). Similar to other ␤-defensins (17), the bactericidal activity of cBD is dependent on the salt concentration used in the in vitro assay (52).…”

Section: Vol 73 2005supporting

confidence: 91%

“…The predicted three-dimensional structure of cBD displaying 3-disulfide bonds (Cys 2 -Cys 29 , Cys 9 -Cys 23 , and Cys 13 -Cys 30 ) was modeled based on the three human ␤-defensins hBD1, -2, and -3 for which experimental structural characterization was available (4). cBD forms a short N-terminal amphipathic alpha-helix (Trp 3 -Arg 6 ) and three-stranded twisted antiparallel beta-sheets formed by Cys 9 -Glu 11 , Ile 21 -Cys 23 , and Leu 28 -Cys 30 , respectively (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

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Molecular Cloning and Characterization of Three β-Defensins from Canine Testes

Sang¹,

Ortega

Blecha³

et al. 2005

Infect Immun

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Mammalian ␤-defensins are small cationic peptides possessing broad antimicrobial and physiological activities. Because dogs are particularly resilient to sexually transmitted diseases, it has been proposed that their antimicrobial peptide repertoire might provide insight into novel antimicrobial therapeutics and treatment regimens. To investigate this proposal, we cloned the full-length cDNA of three canine ␤-defensin isoforms (cBD-1, -2, and -3) from canine testicular tissues. Their predicted peptides share identical N-terminal 65-amino-acid residues, including the ␤-defensin consensus six-cysteine motif. The two longer isoforms, cBD-2 and -3, possess 4 and 34 additional amino acids, respectively, at the C terminus. To evaluate the antimicrobial activity of cBD, a 34-amino-acid peptide derived from the shared mature peptide region was synthesized. Canine ␤-defensin displayed broad antimicrobial activity against gram-positive bacteria (Listeria monocytogenes and Staphylococcus aureus; MICs of 6 and 100 g/ml, respectively), gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Neisseria gonorrhoeae; MICs of 20 to 50, 20, and 50 g/ml, respectively), and yeast (Candida albicans; MIC of 5 to 50 g/ml) and lower activity against Ureaplasma urealyticum and U. canigenitalium (MIC of 200 g/ml). Antimicrobial potency was significantly reduced at salt concentrations higher than 140 mM. All three canine ␤-defensins were highly expressed in testis. In situ hybridization indicated that cBD-1 was expressed primarily in Sertoli cells within the seminiferous tubules. In contrast, cBD-2 was located primarily within Leydig cells. The longest isoform, cBD-3, was detected in Sertoli cells and to a lesser extent in the interstitium. The tissue-specific expression and broad antimicrobial activity suggest that canine ␤-defensins play an important role in host defense and other physiological functions of the male reproductive system. The mucosal physical barrier is an important component protecting luminal surfaces from bacteria. Discovery of epithelium-derived antimicrobial peptides with activity at mucosal surfaces extends luminal protection from the traditional barrier effect to innate immune capabilities. These endogenous peptides are natural antibiotics that are widely distributed in nature and represent an important mechanism of innate defenses against microbial infection (1, 5). Among these naturally occurring antimicrobial peptides, defensins form a unique family of cysteine-rich, small cationic peptides (17).The defensin family is large and has been documented in mammals, plants, insects, and mollusks (6,27,29,39,47). In mammals, defensins are subdivided into ␣-, ␤-, and -defensins based on the organization of conserved six-cysteine motifs (43,50). With the exception of bovine neutrophils, ␤-defensins are synthesized primarily in epithelial tissues (18,27). Because epithelia of the male reproductive tract are essentially isolated from adaptive immune capabilities and because the luminal contents of the testis and...

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Section: Vol 73 2005supporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of Three β-Defensins from Canine Testes

Sang¹,

Ortega

Blecha³

et al. 2005

Infect Immun

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“…Similar increased early inflammation has been noted for defensin-sensitive mutants of NTHi (25). Thus, we compared the two strains for their relative ability to resist complement-mediated killing and the chinchilla beta-defensin cBD-1 (15). There was no detectable increase in in vitro killing by these two mechanisms as a result of the mutation (data not shown).…”

Section: Resultssupporting

confidence: 57%

Phosphorylcholine Decreases Early Inflammation and Promotes the Establishment of Stable Biofilm Communities of Nontypeable Haemophilus influenzae Strain 86-028NP in a Chinchilla Model of Otitis Media

et al. 2007

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Haemophilus influenzae is a gram-negative pleiomorphic bacterium that is a common commensal/mutualist within the human airways (30). Encapsulated H. influenzae strains are overt pathogens causing invasive disease (3) and have largely been contained by a vaccine effective against the predominant capsular serotype b strains (32). In contrast, the so-called nontypeable H. influenzae (NTHi) strains lacking capsular polysaccharides remain predominant in asymptomatic carriage and localized airway infections (14, 29). These infections are mostly opportunistic in nature and include bronchiopneumonia, sinusitis, and otitis media (OM). OM is among the most common pediatric infections, causing an estimated ϳ$5 billion in costs of treatment and parents' missed work days per year (20). OM infections include chronic OM that is difficult to resolve with antibiotic therapy, and it has long been postulated that chronic OM involves the formation of bacterial biofilm communities (5, 35). In support of that hypothesis, biofilms have been visualized in tympanostomy drain tubes removed from patients with OM and on middle ear tissue from experimentally infected chinchillas (7,18,33). More recent evidence shows that NTHi and other bacterial agents are present within biofilms on tissue specimens obtained from patients with chronic and recurrent OM (13).The H. influenzae surface is covered with lipooligosaccharide (LOS) endotoxins that lack a repeating O side chain. Instead, the H. influenzae LOS features a diverse collection of LOS glycoforms that differ in the length, content, and nature of the chemical linkages found in the oligosaccharide portion. These LOS oligosaccharides include structures that are antigenically similar to host cell-surface glycolipids and may also contain the host membrane constituents sialic acid (NeuAc) and phosphorylcholine (PCho) (41). LOS confers resistance to host killing (8,9,37) and is also the primary target of the Toll-like receptor 4 pathway that mediates protection against H. influenzae in the airways (47). It has been established that NTHi strains that express NeuAc-LOS forms comprise a greater proportion of biofilm communities than of planktonic cultures, and that mutations eliminating these forms decrease biofilm formation and bacterial persistence in animal models of OM (4,12,18,43). More recently, we showed that LOS purified from biofilms has decreased potency as an inflammatory agonist, which correlated with an increase in PCho ϩ LOS forms that were present within biofilms (55). In this study, we compared the virulence

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“…This is a widely accepted model of noninvasive disease caused by H. influenzae (1,24,56). An isogenic mutant strain from which the set of three hgp genes had been deleted exhibited a significant reduction in virulence compared to its wild-type progenitor.…”

Section: Discussionmentioning

confidence: 99%

Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

Seale¹,

Morton²,

Whitby³

et al. 2006

Infect Immun

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Haemophilus influenzae requires an exogenous heme source for aerobic growth in vitro. Hemoglobin or hemoglobin-haptoglobin satisfies this requirement. Heme acquisition from hemoglobin-haptoglobin is mediated by proteins encoded by hgp genes. Both Hgps and additional proteins, including those encoded by the hxu operon, provide independent pathways for hemoglobin utilization. Recently we showed that deletion of the set of three hgp genes from a nontypeable strain (86-028NP) of H. influenzae attenuated virulence in the chinchilla otitis media model of noninvasive disease. The present study was undertaken to investigate the role of the hgp genes in virulence of the wild-type serotype b clinical isolate HI689 in the infant rat model of hematogenous meningitis, an established model of invasive disease requiring aerobic growth. Bacteremia of high titer and long duration (>14 days) and histopathologically confirmed meningitis occurred in >95% of infant rats challenged at 5 days of age with strain HI689. While mutations disrupting either the Hgp-or Hxu-mediated pathway of heme acquisition had no effect on virulence in infant rats, an isogenic mutant deficient for both pathways was unable to sustain bacteremia or produce meningitis. In contrast, mutations disrupting either pathway decreased the limited ability of H. influenzae to initiate and sustain bacteremia in weanling rats. Biochemical and growth studies also indicated that infant rat plasma contains multiple heme sources that change with age. Taken together, these data indicate that both the hgp genes and the hxuC gene are virulence determinants in the rat model of human invasive disease.

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Identification and Characterization of a Mucosal Antimicrobial Peptide Expressed by the Chinchilla (Chinchilla lanigera) Airway

Cited by 23 publications

References 34 publications

Molecular Cloning and Characterization of Three β-Defensins from Canine Testes

Molecular Cloning and Characterization of Three β-Defensins from Canine Testes

Phosphorylcholine Decreases Early Inflammation and Promotes the Establishment of Stable Biofilm Communities of Nontypeable Haemophilus influenzae Strain 86-028NP in a Chinchilla Model of Otitis Media

Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

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