Microorganisms which succeed in overcoming the numerous and complex mechanisms of the host immune system are able to invade and grow in the host, thereby causing disease. To escape the host's antimicrobial immunity, the microorganism must evolve mechanisms which are capable of interfering either with the host's innate immune system, the regulatory system of the immune response or with its effector mechanisms. In normal animals immunocompetency is determined by delicate balance of positive and negative signals. If a microorganism disrupts this delicate balance, harmful consequences may occur. When the host is immunocompetent, an invading microorganism may increase the existing imbalance of these signals. Such may be the case with the organism Pseudomonas aeruginosa. P. aeruginosa has a predilection for immunocompromised individuals, those patients which have an imbalance in their normal immune regulatory system. The production of extracellular enzymes and/or toxins by P. aeruginosa appears to play a significant role in the ability of this organism to cause disease. The most toxic substance produced by P. aeruginosa is exotoxin A and thus it may play a significant role in the pathogenicity of the organism. We have previously shown that exotoxin A modulates the murine immune response to a second antigen. Depending on the immunocompetence of the host, exotoxin A may exert its effect through different immune cell populations. This proposal intends to further extend these studies by examining the specific mechanisms by which exotoxin A acts as a biological response modifier. In immunocompetent euthymic (+/nu) mice, we have shown that exotoxin A can suppress the immune response to either thymus dependent or thymus independent antigens by activating a suppressor T cell. Characterization of the suppressor T cell and its suppressor factor(s) will be forthcoming in this proposal. In addition, we have also observed that although exotoxin A does not induce suppression of the immune response to the thymus independent antigen, TNP-Ficoll, in the immunoincompetent athymic nu/nu mice, exotoxin A at higher doses is capable of inducing enhanced immune responses to both thymus independent and thymus dependent antigens in nude mice. This enhanced response was found to be antigen specific and not due to polyclonal B cell activation. We have also observed that exotoxin A is capable of inducing specific cell populations to proliferate both in athymic (nu/nu) mice and in euthymic (+/nu) mice. Experiments to delineate the mechanisms by which exotoxin A induces proliferation of specific cells and enhances nude mice immune responsiveness are outlined in this proposal. These studies should increase our understanding of the mechanisms by which bacterial derived immunomodifiers (i.e., exotoxin A) function as immunomodulatory agents.
