During the course of gonococcal infection of human fallopian tube mucosa in organ culture and in vivo, gonococci attach to the microvilli of non- ciliated epithelial cells, induce sloughing of ciliated cells, and induce their own endocytosis by the non-ciliated cells (""""""""parasite-directed endocytosis""""""""). Gonococci are transported from the luminal pole of the cell to the base of the cell and are exocytosed into the subepithelial tissues where they might cause local disease or enter the blood stream to cause disseminated disease. A number of other human pathogens appear to """"""""invade"""""""" the host by parasite-directed endocytosis. Knowledge of the mechanism of parasite-directed endocytosis might afford a basis for new strategies for intervening in the gonococcal disease process to the advantage of the host. The proposed studies will examine two hypotheses regarding the mechanism of parasite-directed endocytosis: 1) That on their surface the gonococci have molecules which allow the organisms to enter cell by masquerading as a cluster of hormone molecules (""""""""biologic mimicry"""""""" hypothesis) or 2) that lipopolysaccharide or peptidoglycan monomers elaborated by gonococci elicit the production of tumor necrosis factor (TNF) or other biologic mediators which induce the sloughing of ciliated cells and stimulate the non-ciliated cells to elongate their microvilli and to engage in endocytic activity (""""""""biologic mediator"""""""" hypothesis). The testing of both hypotheses will involve the use of an experimental model of human fallopian tubes in organ culture which allows quantitation of intracellular (endocytosed) versus extracellular (attached) gonococci. The first hypothesis will be tested by determining if a blocker of hCG (i.e., anti-hCG antibody) blocks endocytosis. The second hypothesis will be tested by allowing gonococci to attach to fallopian tub epithelium and assessing the qualitative and quantitative effect of recombinant human TNF on the ultrastructural events in the interaction of gonococci with fallopian tube mucosa. We will also evaluate the effect of blocker of TNF (i.e., anti-TNF antibody or dexamethasone) on the endocytosis of gonococci in gonococcus-infected organ cultures with added TNF.
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