Tumor Cell Death Mediated by Peptides That Recognize Branched Intermediates of DNA Replication and Repair

Dey, Mamon; Patra, Sukanya; Su, Leo Y.; Segall, Anca M.

doi:10.1371/journal.pone.0078751

Cited by 13 publications

(9 citation statements)

References 65 publications

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“…Furthermore, colonic histology and faecal microbiome analysis of the peptidetreated mice were unchanged relative to the sham and placebo-treated groups. These findings are consistent with previous reports that show no evidence of cytotoxicity in a variety of human cell lines and murine primary cells exposed to peptide at concentrations below 100 µM (Dey et al, 2013;Su et al, 2010).…”

Section: Discussionsupporting

confidence: 93%

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing

et al. 2016

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Citrobacter rodentium is a Gram-negative, murine-specific enteric pathogen that infects epithelial cells in the colon. It is closely related to the clinically relevant human pathogen, enterohemorrhagic Escherichia coli (EHEC), a leading cause of haemorrhagic colitis and haemolytic uremic syndrome. We have previously reported that a novel antimicrobial peptide, wrwycr, compromises bacterial DNA repair and significantly reduces the survival of acid-stressed EHEC, suggesting an antimicrobial strategy for targeting the survival of ingested EHEC. This study examines the impact of peptide pretreatment on survival of the closely related murine pathogen, C. rodentium, before and after acid stress, using both in vitro and in vivo investigations. Peptide pretreatment of C. rodentium significantly and dramatically increases acid-stress-induced killing in a peptide-dosedependent and time-dependent manner. Reduction in survival rates after brief pretreatment with peptide (25-65 µM) followed by 1 h at pH 3.5 ranges from 6 to 8 log fold relative to untreated C. rodentium, with no detectable bacteria after 65 µM peptide-acid treatment. Using a C57BL/6 mouse model of infection, peptide pretreatment of C. rodentium with wrwycr prior to orogastric gavage eliminates evidence of infection based on C. rodentium colonization levels, faecal scores, colonic histology, faecal microbiome and visual observation of overall animal health. These findings provide compelling evidence for the role of the peptide wrwycr as a potential strategy to control the growth and colonization of enteric pathogens.

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Section: Discussionsupporting

confidence: 93%

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing

et al. 2016

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“…Additionally, colonic histology analysis of peptide-treated mice was unchanged relative to the sham and placebo-treated groups. These findings are consistent with previous reports that show no evidence of cytotoxicity in a variety of human cell lines and murine primary cells exposed to peptide at concentrations below 100µM (Dey et al, 2013;Su et al, 2010). Moreover the in vivo studies revealed that 50-65µM peptide pre-treatment of C. rodentium prior to infection of mice ameliorated any evidence of infection based on C. rodentium colonization levels, fecal scores, colonic histology, and visual observation of overall animal health.…”

Section: A! B! C!supporting

confidence: 92%

Understanding and exploiting the response of EHEC O157:H7 to human gastrointestinal chemical signals

Lackraj¹

2021

Preprint

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Enterohemorrhagic Escherichia coli (EHEC) is a clinically relevant foodborne pathogen, resulting in over 95,000 cases of EHEC-associated illness and 60 deaths each year in the US alone. Since EHEC is a continuous global issue with new outbreaks constantly occurring, the development of new therapeutic strategies is vital to minimizing the cases of infection seen each year. A key aspect in new drug development is the identification of vulnerabilities in EHEC’s pathogenicity, in particular, during its transit through the human gastrointestinal (GI) tract. As EHEC passes through the human GI tract to its site of colonization in the large intestine, it faces a multitude of host assaults including acute acid stress in the stomach, bile salt stress and cationic antimicrobial peptide exposure in the small intestine, and short chain fatty acid (SCFA) stress in the large intestine. The research carried out in this doctoral dissertation focuses on understanding how EHEC senses chemical cues from the host’s innate immune responses and how this knowledge can be exploited to develop effective antimicrobial strategies. Our findings successfully demonstrate that a novel antimicrobial peptide ameliorates infection in a mouse model of infection by enhancing acid-induced pathogen killing during gastric passage, and that the DNAbinding protein, Dps, plays a significant role in protecting EHEC against peptide killing. Moreover, this research successfully shows that varying concentrations of SCFAs result in differential modulation of EHEC virulence – a finding that contributes to our understanding of the role of diet and commensal flora in host susceptibility to infection. Together the findings of this research demonstrate how the selected innate host defences throughout the human GI tract can be exploited and/or manipulated to effectively prevent infection by the human pathogen EHEC.

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“…Cell viability was determined by the methylthiazolyl-diphenyl-tetrazolium bromide (MTT) assay as described previously [ 32 ]. Briefly, after stimulation of cells with various concentrations of peptides (1–25 μg/ml) in six-well plates for 48 h, MTT solution was added to each well.…”

Section: Methodsmentioning

confidence: 99%

Cleavage of Host Cytokeratin-6 by Lysine-Specific Gingipain Induces Gingival Inflammation in Periodontitis Patients

et al. 2015

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Background/PurposeLysine-specific gingipain (Kgp) is a virulence factor secreted from Porphyromonas gingivalis (P. gingivalis), a major etiological bacterium of periodontal disease. Keratin intermediate filaments maintain the structural integrity of gingival epithelial cells, but are targeted by Kgp to produce a novel cytokeratin 6 fragment (K6F). We investigated the release of K6F and its induction of cytokine secretion.MethodsK6F present in the gingival crevicular fluid of periodontal disease patients and in gingipain-treated rat gingival epithelial cell culture supernatants was measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometer-based rapid quantitative peptide analysis using BLOTCHIP. K6F in gingival tissues was immunostained, and cytokeratin 6 protein was analyzed by immunofluorescence staining and flow cytometry. Activation of MAPK in gingival epithelial cells was evaluated by immunoblotting. ELISA was used to measure K6F and the cytokines release induced by K6F. Human gingival fibroblast migration was assessed using a Matrigel invasion chamber assay.ResultsWe identified K6F, corresponding to the C-terminus region of human cytokeratin 6 (amino acids 359–378), in the gingival crevicular fluid of periodontal disease patients and in the supernatant from gingival epithelial cells cultured with Kgp. K6F antigen was distributed from the basal to the spinous epithelial layers in gingivae from periodontal disease patients. Cytokeratin 6 on gingival epithelial cells was degraded by Kgp, but not by Arg-gingipain, P. gingivalis lipopolysaccharide or Actinobacillus actinomycetemcomitans lipopolysaccharide. K6F, but not a scrambled K6F peptide, induced human gingival fibroblast migration and secretion of interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1. These effects of K6F were mediated by activation of p38 MAPK and Jun N-terminal kinase, but not p42/44 MAPK or p-Akt.ConclusionKgp degrades gingival epithelial cell cytokeratin 6 to K6F that, on release, induces invasion and cytokine secretion by human gingival fibroblasts. Thus, Kgp may contribute to the development of periodontal disease.

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Tumor Cell Death Mediated by Peptides That Recognize Branched Intermediates of DNA Replication and Repair

Cited by 13 publications

References 65 publications

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing

Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing

Understanding and exploiting the response of EHEC O157:H7 to human gastrointestinal chemical signals

Cleavage of Host Cytokeratin-6 by Lysine-Specific Gingipain Induces Gingival Inflammation in Periodontitis Patients

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