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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI060641-04
Application #
7219976
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Duncan, Rory A
Project Start
2004-07-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$129,330
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Ibrahim, Ashraf S; Edwards Jr, John E; Bryant, Richard et al. (2009) Economic burden of mucormycosis in the United States: can a vaccine be cost-effective? Med Mycol 47:592-600
Spellberg, Brad; Talbot, George H; Boucher, Helen W et al. (2009) Antimicrobial agents for complicated skin and skin-structure infections: justification of noninferiority margins in the absence of placebo-controlled trials. Clin Infect Dis 49:383-91
Spellberg, Brad; Andes, David; Perez, Mario et al. (2009) Safety and outcomes of open-label deferasirox iron chelation therapy for mucormycosis. Antimicrob Agents Chemother 53:3122-5
Spellberg, Brad; Walsh, Thomas J; Kontoyiannis, Dimitrios P et al. (2009) Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 48:1743-51
Lin, Lin; Ibrahim, Ashraf S; Baquir, Beverlie et al. (2009) Immunological surrogate marker of rAls3p-N vaccine-induced protection against Staphylococcus aureus. FEMS Immunol Med Microbiol 55:293-5
Spellberg, Brad; Talbot, George H; Brass, Eric P et al. (2008) Position paper: recommended design features of future clinical trials of antibacterial agents for community-acquired pneumonia. Clin Infect Dis 47 Suppl 3:S249-65
Spellberg, Brad; Fleming, Thomas R; Gilbert, David N (2008) Executive summary: workshop on issues in the design and conduct of clinical trials of antibacterial drugs in the treatment of community-acquired pneumonia. Clin Infect Dis 47 Suppl 3:S105-7
Ibrahim, Ashraf S; Gebremariam, Teclegiorgis; Fu, Yue et al. (2008) Combination echinocandin-polyene treatment of murine mucormycosis. Antimicrob Agents Chemother 52:1556-8
Reed, Caitlin; Bryant, Richard; Ibrahim, Ashraf S et al. (2008) Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 47:364-71
Ibrahim, Ashraf S; Gebremariam, Teclegiorgis; Liu, Mingfu et al. (2008) Bacterial endosymbiosis is widely present among zygomycetes but does not contribute to the pathogenesis of mucormycosis. J Infect Dis 198:1083-90

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