MACROPHAGE RESPONSES TO BACTERIAL TOXINS

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DESCRIPTION (Adapted from the applicant's abstract): The proposed studies will examine the causes of misregulation of macrophage inflammatory responses. Pathogen-phagocytes interactions are critical in many infectious diseases. A newly recognized bacterial pathogen strategy is the expression of toxins which upregulate inflammatory functions which directly mediate acute pathologies and symptoms. Hyperstimulation of important macrophage functions by toxin was first described using the anthrax system. Anthrax lethal toxin mimics all the symptoms of systemic anthrax including death. Upon entering the macrophage, the toxin induces an extreme oxidative burst producing oxygen radicals (ROI) which rupture cell membranes. Lethal toxin also induces overexpression of TNF_ and IL-1_ which directly cause symptoms and death in BALB/c mice. Macrophage-depleted mice are toxin-resistant. This well-defined model will be used to uncover patterns of key regulatory points of the lethal inflammatory process. The first goal is to identify macrophage target proteins for the lethal toxin protease activity using combinatorial chemistry techniques and to understand their role in mediating inflammation. The second major aim is to elucidate the role of the anthrax toxin receptor in this process. It is proposed to clone the receptor gene from _gt11 macrophage cDNA libraries and to determine sequence, receptor number and natural functions. The third aim will examine the signaling relationship between ROIs and initiation of immuno-specific macrophage gene expression. NF_B will be examined as a signaling element inking the two events. It is becoming apparent that highly targeted disruption of the normal regulation of immune cell antimicrobial functions by bacterial factors induce overexpression of host mediators of septic shock, acute respiratory distress syndrome and other pathologies seen during infections. Activation of the same systems contribute to autoimmune and chronic inflammatory disorders. This proposal examines key molecular aspects of these regulated pathways.