Chemoreceptors Control Salmonella Typhimurium Motility, Accumulation, and Localization in in Vitro Tumors
Rachel W. Kasinskas, University of Massachusetts, 686 N. Pleasant St., 61 Goessmann Lab, Amherst, MA 01003 and Neil S. Forbes, Chemical Engineering, University of Massachusetts, 686 N. Pleasant St., 61 Goessmann Lab, Amherst, MA 01003.
Multi-drug resistance greatly limits the efficacy of conventional blood-born chemotherapeutics that have limited ability to penetrate tumor tissue and are ineffective at killing quiescent cells far from tumor vasculature. Nonpathogenic, motile bacteria can overcome both of theses limitations. We hypothesize that the chemotaxis machinery of S. typhimurium is essential for chemotaxis and accumulation within cylindroids. We also hypothesize that there may be a single surface receptor responsible for chemotaxis towards cylindroids, and that all components of the chemotaxis machinery are necessary for accumulation within cylindroids. We tested these hypotheses by observing the interaction of chemotaxis-deficient mutants using the tumor cylindroid model, which mimics the microenvironments of in vivo tumors. Time-lapse fluorescence microscopy was used to measure the accumulation of GFP-labeled S. typhimurium into cylindroids. The presence of one particular receptor was necessary for chemotaxis towards tumor cylindroids, and the presence of other receptors direct the location of chemotaxis and colonization of S. typhimurium inside tumor cylindroids. The presence of a specific ligand gradient at the cylindroid edge directs S. typhimurium to chemotaxis towards tumor cylindroids through its respective receptor. Mutant strains that lacked the proper flagella construct or motor function and strains with inactive signal transduction proteins do not chemotax towards tumor cylindroids. By understanding which aspects of the chemotaxis machinery control accumulation in tumor cylindroids, we plan to develop bateriolytic therapies with improved targeting to therapuetically inaccessible regions and metastic lesions.