Bacterial host interactions in cystic fibrosis

Callaghan, Máire; McClean, Siobhán

doi:10.1016/j.mib.2011.11.001

Cited by 45 publications

(41 citation statements)

References 64 publications

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“…While CF is a neutrophildominated disease and the resultant high levels of NE contribute to morbidity (10,11), it may be unfavorable to kill immune cells when a patient is suffering from a potentially severe infection. If the mechanism of cell death is necrosis, this could lead to the release of extracellular DNA in patients with CF, which increases mucus viscosity and facilitates bacterial attachment (13).…”

Section: Figmentioning

confidence: 99%

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Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Forde

Schutte

Reeves

et al. 2016

Antimicrob Agents Chemother

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There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o-cells, >300 M) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ؎ 6.9% alone to 91.5% ؎ 5.8% with BAL fluid; P ‫؍‬ 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.

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Section: Figmentioning

confidence: 99%

“…The nonresolving inflammatory response leads to long-term reductions in lung function and is associated with premature death (7,8,13). Neutrophils represent approximately 70% of the airway inflammatory cell population in patients with CF but only 1% of the airway inflammatory cell population in healthy individuals (14).…”

mentioning

confidence: 99%

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Forde

Schutte

Reeves

et al. 2016

Antimicrob Agents Chemother

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“…This bacterial pathogen complex comprises a group of 20 species of Gram-negative bacteria (8-11), 2 of which, Burkholderia multivorans and B. cenocepacia, are the most clinically relevant (12,13). Members of the Bcc are reported to cause infections in up to 5% of cystic fibrosis (CF) patients in the world, which is significant, as CF patients colonized with Bcc experience a more rapid decline than do those colonized with the more commonly acquired pathogen Pseudomonas aeruginosa (14,15). Once a patient is colonized with Bcc bacteria, these bacteria are rarely eradicated due to the resistance of the Bcc to antibiotics (16) and antimicrobial peptides (17,18).…”

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confidence: 99%

Linocin and OmpW Are Involved in Attachment of the Cystic Fibrosis-Associated Pathogen Burkholderia cepacia Complex to Lung Epithelial Cells and Protect Mice against Infection

McClean¹,

Healy

Collins³

et al. 2016

Infect Immun

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Members of the Burkholderia cepacia complex (Bcc) cause chronic opportunistic lung infections in people with cystic fibrosis (CF), resulting in a gradual lung function decline and, ultimately, patient death. The Bcc is a complex of 20 species and is rarely eradicated once a patient is colonized; therefore, vaccination may represent a better therapeutic option. We developed a new proteomics approach to identify bacterial proteins that are involved in the attachment of Bcc bacteria to lung epithelial cells. Fourteen proteins were reproducibly identified by two-dimensional gel electrophoresis from four Bcc strains representative of two Bcc species: Burkholderia cenocepacia, the most virulent, and B. multivorans, the most frequently acquired. Seven proteins were identified in both species, but only two were common to all four strains, linocin and OmpW. Both proteins were selected based on previously reported data on these proteins in other species. Escherichia coli strains expressing recombinant linocin and OmpW showed enhanced attachment (4.2-and 3.9-fold) to lung cells compared to the control, confirming that both proteins are involved in host cell attachment. Immunoproteomic analysis using serum from Bcc-colonized CF patients confirmed that both proteins elicit potent humoral responses in vivo. Mice immunized with either recombinant linocin or OmpW were protected from B. cenocepacia and B. multivorans challenge. Both antigens induced potent antigen-specific antibody responses and stimulated strong cytokine responses. In conclusion, our approach identified adhesins that induced excellent protection against two Bcc species and are promising vaccine candidates for a multisubunit vaccine. Furthermore, this study highlights the potential of our proteomics approach to identify potent antigens against other difficult pathogens.

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“…Bacterial infection begins soon after birth and is followed by an intense neutrophilic response in the peribronchial and endobronchial spaces, releasing large amounts of neutrophil elastase (NE) (1,2). By far the most significant pathogen in adult CF infection is Pseudomonas aeruginosa, often causing chronic, endobronchial, drug-resistant infection (3)(4)(5)(6).…”

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confidence: 99%

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

Forde

Humphreys

Greene

et al. 2014

Antimicrob Agents Chemother

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Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of Pseudomonas aeruginosa to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of P. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 g/ml). Cytotoxic effects on CFBE41o-cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at in vivo concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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Bacterial host interactions in cystic fibrosis

Cited by 45 publications

References 64 publications

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Differential In Vitro and In Vivo Toxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis

Linocin and OmpW Are Involved in Attachment of the Cystic Fibrosis-Associated Pathogen Burkholderia cepacia Complex to Lung Epithelial Cells and Protect Mice against Infection

Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

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