The long term objectives of this program are to define, at molecular and cellular levels, interactions between bacteria and mammalian cells. The focus is on: (1) Biochemical changes phagocytic leukocytes undergo when they ingest a bacterium (or are otherwise stimulated) - insofar as these changes are part of the leukocyte's anti-bacterial armamentarium; (ii) The effect on the host organism's cells of substances released as a result of phagocytic killing and dismantling of the bacterium. In the first context, release of active oxygen radicals by phagocytic leukocytes is the main focus, and is in the mainstream of studies of control of infection. In the second context the focus is on the effect on mammalian cells of muramyl peptides (components of the bacterial cell wall) that are released from engulfed bacteria (and also by enzyme action on dead bacteria of the gut). The latter substances are known to stimulate the host immune system. They also are fever-inducing. Finally, they are somnogenic (i.e., promote slow-wave sleep). The last mentioned consideration is neglected in the mainstream of investigations of infection. Experiments to achieve the goals outlined consist in isolating appropriate mammalian cells, and in the first context, stimulating them in a variety of ways while following release of superoxide and monitoring other cellular, especially membrane, functions. In the second category, the questions have developed into considerations of the mechanism(s) by which muramyl peptides induce physiological changes in mammalian cells - i.e., the matter has progressed from the """"""""whole-animal"""""""" effect (e.g., slow- wave sleep induction) to the cellular level - in particular, studies of specific cellular binding sites (receptors?) for muramyl peptides and sequels of binding. A key matter is that muramyl peptides (immunostimulants) and serotonin (a neuro- transmitter) compete for the same cellular binding sites, and induce several responses in common. In addition, B-lymphocytes of narcoleptics (who have a derangement of normal sleep) do not bind muramyl peptides in contradistinction to cells of normals. Since narcolepsy is characterized by a specific immune situation (expression of histocompatibility antigen DR2, DQwl) this constitutes a further link between the immune and neurological systems. These matters are health-related in that they deal with the host's antimicrobial mechanisms, and with secondary effects of bacterial death, i.e., neuro-immune interactions due to bacterial breakdown products.
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