Funktion von IL-17 in Giardiasis: Identifizierung von IL-17-produzierenden Zellen, Induktionsmechanismen und Funktion von IL-17 im adaptiven Immunsystem in Giardiasis
Final Report Abstract
Enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium are attaching and effacing pathogens that cause intestinal inflammation and diarrhea in susceptible hosts. The bacteria adhere to the intestinal epithelium, destroy microvilli and induce characteristic actinfilled membranous pedestals, but do not invade deeply into the mucosa. Adherence is accompanied by activation of several host cells kinases, including c-Fyn, n-Src, Yes and the Abl-family kinases ABL and ARG, leading to phosphorylation of the bacterial translocated intimin receptor and actin polymerization and pedestal formation in cell culture models. However, marked functional kinase redundancy appears to exist, and their physiological importance in A/E pathogen infections has remained unclear. To address this question, we have employed a novel dynamic in vitro infection model that mimics transient and short-term interactions in the intestinal tract, and conditional gene-targeted mice. Screening of a kinase inhibitor library and targeted exploration of specific kinases in vivo revealed that ABL, p38 MAP kinase, and PDGF receptor kinase have unique, indispensable roles in attachment of EPEC and C. rodentium to epithelial cells under physiological conditions. Furthermore, inhibition of ABL, ARG, or p38 MAPK delayed or prevented mucosal attachment and infectivity for modest bacterial loads. These kinases were dispensable for high inocula or late after infection. ABL and ARG also had important host protective functions, since their combined loss in the intestinal epithelium compromised normal mucosal integrity and general health, and led to severe intestinal damage. For future therapeutic implications kinase functions has to be carefully assessed and reasonable balancing of beneficial and detrimental effects will become necessary to determine whether such strategy can ultimately be employed in a clinical setting.
Publications
- DDW: Epithelial cell signaling as target for antimicrobial therapy against diarrheagenic Escherichia coli – new role for kinase inhibitors in blocking infections with enteropathogenic E. coli. May 2012, San Diego, California, USA
Manthey CF, Eckmann L
