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Projekt
Mechanism of impairment of testicular function by immune evasive mechanism of uropathogenic Escherichia coli (UPEC)
Antragsteller
Professor Dr. Trinad Chakraborty; Professor Dr. Andreas Meinhardt
Fachliche Zuordnung
Reproduktionsmedizin, Urologie
Förderung
Förderung von 2008 bis 2015
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 34016037
E. coil based infection is an established major factor for male infertility. In Sertoli cells (SC), peritubular cells (PTC) and testicular macrophages (TM) the pro-inflammatory NFKB pathway is blocked downstream at different levels following infection with uropathogenic E. coli (UPEC) resulting in inhibited secretion of pro-inflammatory cytokines. Infected cells respond with nuclear factor of activated T cells (NFAT)C2 signaling as alternative pathway, however, leading to an anti-inflammatory Th2 type response. We aim to investigate if UPEC can silence NFKB regulated pro-inflammatory gene transcription by NFAT activated histone deacetylases (HDAC1) chromatin remodeling. Moreover, an influence of UPEC on peroxisome proliferator activated receptor (PPAR)y to repress NpKB-mediated inflammatory response will be investigated. An established rat in vivo orchitis infection model will be used to link our in vitro studies and the human biopsy investigations. Extra- and intracellular persistence of UPEC and mutants will be monitored to provide information up to what time post-infection UPEC may be detectable in biopsy specimens to help guiding diagnosis. Initial results show the presence of bacterial DNA in testis biopsies with inflammatory infiltrates, but could not reveal the species. New automated sample extraction combined with DHPLCbased profiling and subsequent sequencing of microbial marker genes allows discrimination of uropathogens and opportunistic bacteria. In vivo UPEC immunosuppressive properties seen in vitro shall be validated e.g. by examining the hypothesized shift from a Thi to a Th2 immune response. The role of reproductive tract specific antimicrobial peptides (isoforms of SPAG11 & beta-defensins) will be examined by substitution in the in vivo infection model.
DFG-Verfahren
Klinische Forschungsgruppen
