This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The dogma of an immune response is built around the idea that the immune system can discriminate between self and non-self, based largely on B-cell and T-cell selection during early fetal or neonatal life. This model proposes that the cells of the immune system 'rub elbows' with any cells present at this time (including foreign cells) as they are maturing and through this process 'learn' not to react to these cells. This model has failed to convincingly explain why the immune system does not respond to antigens that are newly expressed in later life stages including puberty and pregnancy. An emerging alternative model, championed by Polly Matzinger of the NIH in Bethesda, MD., theorizes that the self vs. non-self model is inaccurate and proclaims that our immune system does not respond to non-self but instead responds to 'danger signals' released by damaged cells. This model provides a logical explanation as to why an immune response is elicited for only a limited number of bacteria despite the fact that we are in contact with large varieties of organisms, both internally and externally, on a daily basis. The question then arises, what signal would our immune system utilize as a means of sensing 'danger' or cell damage? One possibility is the exposure of hydrophobic surfaces normally hidden within the membrane structure of the cell. If this hypothesis holds true, one could predict that rapid removal of hydrophobic substances from damaged tissue would squelch the immune response. Research in our lab has revealed that both high virulent and low virulent strains of Listeria monocytogenes transcribe phosphotidylinositol-specific phospholipase C (plcA) inconsistently and in contrast to previously defined mechanisms of regulation. The potential remains that highly virulent strains are successful due to its ability to produce a plcA protein capable of rapid phosphotidylinositol degradation, thus preventing a cell from receiving 'danger signals' and preventing an immune response. This is supported by results with low virulent L. monocytogenes, which transcribes a number of virulence genes (hly, actA, prfA) but fails to transcribe plcA under low glucose conditions, perhaps allowing the immune response to be trigger, clearing the infection.
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