Candida is a prominent nosocomial fungal pathogen that causes an unacceptably high mortality (40%) during dissemination, even with antifungal therapy. As well, Candida spp. are increasingly resistant to current antifungal agents. Hence new therapeutic modalities for such infections are critically needed. As Candida infects patients with compromised host defenses, immunotherapies are attractive prospects to serve as adjuncts to antifungal agents. We and others have found that Type 1 immunity protects the host against Candida infections, while Type 2 immunity increases host susceptibility. Because adrenergic antagonism is known to potentiate Type 1 immunity and downregulate Type 2 immunity, we studied its effect during murine disseminated candidiasis and found that it significantly improved survival. The studies herein proposed will define the mechanisms of protection of adrenergic antagonism during murine disseminated candidiasis. The effect of adrenergic antagonism on in vivo cytokine profiles will be defined. The cell type(s) mediating the protective effect will be identified. Finally, in vivo abrogation of Type 1 immunity and modulation of adrenergic signal transduction will be performed during infection to determine the impact on the protective effect of adrenergic antagonism. In addition to the proposed experiments, core training in fundamental immunology and the responsible conduct of research will be achieved via a formal curriculum of graduate-level didactic courses through the UCLA Department of Microbiology, Immunology, and Genetics, and the Harbor-UCLA General Clinical Research Center. Manuscript preparation, regular meetings with an academic advisory committee, and presentations at lab meetings and international conferences will prepare the applicant for a career in academic biomedical research. The tested hypothesis will lead to the establishment of a research path tailored to the applicant's interest in fimgal pathogenesis and host response. Adrenergic antagonists are worthy of study as immunotherapeutic agents because they are inexpensive, have a well-proven safety record after decades of clinical use, and, unlike anti-fungal agents, their immunopotentiation effects are not subject to development of microbial resistance. For these reasons, the potential for adrenergic antagonism to act as an effective immunotherapy is highly meritorious of investigation in this training application.
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