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The Role of EspH and Host Cell Proteins in Enteropathogenic Escherichia Coli-Induced Cell Death and Virulence
Enteropathogenic Escherichia coli (EPEC) is a leading cause of infantile diarrhea, particularly in developing countries. EPEC belongs to the attaching and effacing (A/E) family of pathogens and harbors a type III secretion system (T3SS) that delivers virulence proteins directly into host epithelial cells. These proteins alter host structure and function, likely facilitating pathogenesis. We recently demonstrated that EspH, an EPEC secreted protein, is a critical virulence factor and that mutant strains lacking espH are impaired for pathogenesis. EspH induces host cell death through activation of caspases and mitochondrial fission. We hypothesizes that a wide range of host proteins are implicated in this cell death phenotype. Quantitation of host cell death during EPEC infection using siRNA-mediated knockdown of individual host cell proteins supports this hypothesis. A broad group of host protein knockdowns displayed altered host cell death during infection. The goal of my studies is to identify the host pathway(s) altered during EspH-induced epithelial cell death and, eventually, to establish the significance of this pathway in EPEC virulence.Release after 30-Apr-2024Originally set to release after 10-May-2020; contacted by author on 03-May-2019 to extend embargo through 30-Apr-2024, Kimberl
Un Ă©tat de la recherche sur la noblesse castillane Ă la fin du Moyen Age : Beceiro Pita (Isabel) y Cordoba de la Llave (Ricardo), Parentesco, poder y mentalidad. La nobleza castellana, siglos XII-XV, Madrid, C.S.I.C., 1990
Leroy Béatrice. Un état de la recherche sur la noblesse castillane à la fin du Moyen Age : Beceiro Pita (Isabel) y Cordoba de la Llave (Ricardo), Parentesco, poder y mentalidad. La nobleza castellana, siglos XII-XV, Madrid, C.S.I.C., 1990. In: Annales du Midi : revue archéologique, historique et philologique de la France méridionale, Tome 103, N°195, 1991. pp. 379-380
An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection
Morbidity and mortality attributed to Clostridium difficile infection (CDI) have increased over the past 20 years. Currently, antibiotics are the only US FDA-approved treatment for primary C. difficile infection, and these are, ironically, associated with disease relapse and the threat of burgeoning drug resistance. We previously showed that non-toxin virulence factors play key roles in CDI, and that colonization factors are critical for disease. Specifically, a C. difficile adhesin, Surface Layer Protein A (SlpA) is a major contributor to host cell attachment. In this work, we engineered Syn-LAB 2.0 and Syn-LAB 2.1, two synthetic biologic agents derived from lactic acid bacteria, to stably and constitutively express a host-cell binding fragment of the C. difficile adhesin SlpA on their cell-surface. Both agents harbor conditional suicide plasmids expressing a codonoptimized chimera of the lactic acid bacterium's cell-wall anchoring surface-protein domain, fused to the conserved, highly adherent, host-cell-binding domain of C. difficile SlpA. Both agents also incorporate engineered biocontrol, obviating the need for any antibiotic selection. Syn-LAB 2.0 and Syn-LAB 2.1 possess positive biophysical and in vivo properties compared with their parental antecedents in that they robustly and constitutively display the SlpA chimera on their cell surface, potentiate human intestinal epithelial barrier function in vitro, are safe, tolerable and palatable to Golden Syrian hamsters and neonatal piglets at high daily doses, and are detectable in animal feces within 24 h of dosing, confirming robust colonization. In combination, the engineered strains also delay (in fixed doses) or prevent (when continuously administered) death of infected hamsters upon challenge with high doses of virulent C. difficile. Finally, fixeddose Syn-LAB ameliorates diarrhea in a non-lethal model of neonatal piglet enteritis. Taken together, our findings suggest that the two synthetic biologics may be effectively employed as non-antibiotic interventions for CDI.National Institutes of Health [AI121590]; US Department of Veterans Affairs [1I01BX001183-01]; USDA CSREES Hatch Program [ARZT-570410-A-02-139]; Asset Development Award from Tech Launch ArizonaOpen access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]