Enteric alpha defensins in norm and pathology

Лисицын, Н. А.; Bukurova, Yulia A; Nikitina, I. G.; Krasnov, George S.; Sykulev, Yuri; Beresten, S. F.

doi:10.1186/1476-0711-11-1

Cited by 46 publications

(43 citation statements)

References 100 publications

(67 reference statements)

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“…Our data also suggest that Caco-2 cells can cleave pro-HD5 into active forms. This is in line with previous reports that colon cancers express proteases capable of cleaving HD5 (14,15).…”

Section: Resultssupporting

confidence: 93%

“…The expression of HD5 mRNA and protein in colon cancer has been reported previously (14,15). In our study, we demonstrate the presence of processed HD5 peptides in epithelial ovarian cancer, predominantly in cases of endometrioid cancer.…”

Section: Discussionsupporting

confidence: 80%

“…The ␤-actin gene (forward primer, 5=-CGT CTTCCCCTCCATCG; reverse primer, 5=-CTCGTTAATGTCACGCAC) was used as a reference gene to normalize HD5 mRNA expression. Relative expression levels were calculated using the 2 ϪΔΔCT (where C T is threshold cycle) method (14). qPCR for adenoviral DNA genomes.…”

Section: Methodsmentioning

confidence: 99%

“…Although there are no reports of airway epithelial cells expressing HD5, the epithelial lining fluid of the lung contains 0.3 M HD5, suggesting a potential function in blocking microbes in the airway tract (13). Two studies report that HD5 peptide is present in colon cancer and most likely produced by malignant Paneth cells (14,15). HD5 expression was also documented in the colon cancer cell line Caco-2 where HD5 gene expression can be increased by recombinant fibroblast growth factor 9 (FGF9) (16).…”

mentioning

confidence: 99%

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Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

Vragniau

Hübner

Beidler

et al. 2017

J Virol

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Defensins are small antimicrobial peptides capable of neutralizing human adenovirus (HAdV) in vitro by binding capsid proteins and blocking endosomal escape of virus. In humans, the alpha defensin HD5 is produced by specialized epithelial cells of the gastrointestinal and genito-urinary tracts. Here, we demonstrate, using patient biopsy specimens, that HD5 is also expressed as an active, secreted peptide by epithelial ovarian and lung cancer cells in situ. This finding prompted us to study the role of HD5 in infection and spread of replication-competent, oncolytic HAdV type 3 (HAdV3). HAdV3 produces large amounts of penton-dodecahedra (PtDd), virus-like particles, during replication. We have previously shown that PtDd are involved in opening epithelial junctions, thus facilitating lateral spread of de novo-produced virions. Here, we describe a second function of PtDd, namely, the blocking of HD5. A central tool to prove that viral PtDd neutralize HD5 and support spread of progeny virus was an HAdV3 mutant virus in which formation of PtDd was disabled (mut-Ad3GFP, where GFP is green fluorescent protein). We demonstrated that viral spread of mut-Ad3GFP was blocked by synthetic HD5 whereas that of the wild-type (wt) form (wt-Ad3GFP) was only minimally impacted. In human colon cancer Caco-2 cells, induction of cellular HD5 expression by fibroblast growth factor 9 (FGF9) significantly inhibited viral spread and progeny virus production of mut-Ad3GFP but not of wt-Ad3GFP. Finally, the ectopic expression of HD5 in tumor cells diminished the in vivo oncolytic activity of mut-Ad3GFP but not of wt-Ad3GFP. These data suggest a new mechanism of HAdV3 to overcome innate antiviral host responses. Our study has implications for oncolytic adenovirus therapy. IMPORTANCE Previously, it has been reported that human defensin HD5 inactivates specific human adenoviruses by binding to capsid proteins and blocking endosomal escape of virus. The central new findings described in our manuscript are the following: (i) the discovery of a new mechanism used by human adenovirus serotype 3 to overcome innate antiviral host responses that is based on the capacity of HAdV3 to produce subviral penton-dodecahedral particles that act as decoys for HD5, thus preventing the inactivation of virus progeny produced upon replication; (ii) the demonstration that ectopic HD5 expression in cancer cells decreases the oncolytic efficacy of a serotype 5-based adenovirus vector; and (iii) the demonstration that epithelial ovarian and lung cancers express HD5. The study improves our understanding of how adenoviruses establish infection in epithelial tissues and has implications for cancer therapy with oncolytic adenoviruses.KEYWORDS adenovirus, cancer, defensins, innate immunity

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“…Our data also suggest that Caco-2 cells can cleave pro-HD5 into active forms. This is in line with previous reports that colon cancers express proteases capable of cleaving HD5 (14,15).…”

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

Vragniau

Hübner

Beidler

et al. 2017

J Virol

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“…Furthermore, it was reported that Prochlorperazine (ZINC19796018), an antipsychotic drug with MCS Tanimoto similarity of 0.8276 with Trifluoperazine dihydrochloride (ZINC19418959), also possesses antibacterial activity against several species [39]. Similar studies show evidence that statins, including Rosuvastatin calcium (ZINC01535101), also present activity against a range of bacterial species [40,41]. Proglumetacin maleate (ZINC85537089) belongs to the acetic acid derivatives and related substances class.…”

Section: Resultsmentioning

confidence: 99%

Computational Discovery of Putative Leads for Drug Repositioning through Drug-Target Interaction Prediction

2016

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De novo experimental drug discovery is an expensive and time-consuming task. It requires the identification of drug-target interactions (DTIs) towards targets of biological interest, either to inhibit or enhance a specific molecular function. Dedicated computational models for protein simulation and DTI prediction are crucial for speed and to reduce the costs associated with DTI identification. In this paper we present a computational pipeline that enables the discovery of putative leads for drug repositioning that can be applied to any microbial proteome, as long as the interactome of interest is at least partially known. Network metrics calculated for the interactome of the bacterial organism of interest were used to identify putative drug-targets. Then, a random forest classification model for DTI prediction was constructed using known DTI data from publicly available databases, resulting in an area under the ROC curve of 0.91 for classification of out-of-sampling data. A drug-target network was created by combining 3,081 unique ligands and the expected ten best drug targets. This network was used to predict new DTIs and to calculate the probability of the positive class, allowing the scoring of the predicted instances. Molecular docking experiments were performed on the best scoring DTI pairs and the results were compared with those of the same ligands with their original targets. The results obtained suggest that the proposed pipeline can be used in the identification of new leads for drug repositioning. The proposed classification model is available at http://bioinformatics.ua.pt/software/dtipred/.

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