Infectious Diseases:
Affiliations:
David O. Beenhouwer, MD
Professor of Medicine in Residence, UCLA School of Medicine
Staff Infectious Diseases Specialist, VA Greater Los Angeles Healthcare System
Division of Infectious Diseases, 111F
11301 Wilshire Blvd.
VA Greater Los Angeles Healthcare System
Los Angeles, CA 90073
Tel: (310) 268-3015
Fax: (310) 268-4928
dbeenhou@ucla.edu
RESEARCH INTERESTS:
Targeted delivery of immunostimulatory molecules for treatment and prevention of Cryptococcus neoformans infection - C. neoformans is an encapsulated yeast that causes a chronic central nervous system infection carrying a 10-20% mortality rate. Th1 and proinflammatory cytokines are important in controlling cryptococcosis and protection depends on cell-mediated immunity and an effective granulomatous response. To date, vaccines against C. neoformans have not been effective. Some cytokines show efficacy for treating cryptococcosis. However, the therapeutic use of cytokines is limited by two factors: i) dose-related toxicity, which may preclude delivery of adequate local concentrations, and ii) the instability of cytokines, which results in rapid degradation and very short half-lives. Our laboratory has constructed antibody-cytokine fusion proteins as novel treatment and vaccine adjuvants for cryptococcal infection. We are testing two general hypotheses. First, that the antibody portion will target attenuated organism to antigen presenting cells (APCs) and, in conjunction with the associated cytokine, stimulate effective immune responses against C. neoformans (vaccination). Second, that during active infection, antibody recognizing a pathogen surface antigen will target cytokines to the infectious microenvironment and either shift the Th1-Th2 balance favorably, stimulate an active immune response against the inciting pathogen, or both (therapeutic). These studies are funded by a 4-year VA Merit Review commencing in October 2007 and a 5-year NIH R01 commencing in March 2008.
Role of Panton-Valentine leucocidin (PVL) in CA-MRSA pathogenesis - About 90% of CA-MRSA carry genes for PVL. This bicomponent toxin binds to human neutrophils and monocytes with high affinity and has been associated with furunculosis, necrotizing pneumonia and necrotizing fasciitis. We have generated monoclonal antibodies (mAbs) against PVL, which we are using to define the role of PVL in CA-MRSA pathogenesis. We are also examining these mAbs as novel therapeutics and diagnostic tools for CA-MRSA infection. These studies are currently funded by small industry grants.
Antidote for botulism - Clostridium botulinum neurotoxin (BoNT) is a zinc protease that cleaves proteins involved in presynaptic acetylcholine release, thereby causing paralysis. BoNT is a CDC Category A bioweapon. While prompt administration of antitoxin can prevent intoxication and disease progression, an antidote is urgently needed that can reverse botulinum toxin neuromuscular paralysis once it has occurred. We have produced inactive BoNT (iBoNT) by mutating amino acids in the zinc coordination region. We have already demonstrated that iBoNT inhibits native BoNT activity in vitro. We postulate that, like the native toxin, iBoNT will enter cholinergic neurons and compete for the same substrate as BoNT, but will not cleave it. We propose to develop iBoNT as the first antidote for botulism. Grant support is pending for this project.
Other Interests - I also have clinical interests in the applications of IVIg for infections and the infectious complications of biologic agents such as the anti-TNF therapeutics.
Click to see publications by David Beenhouwer
SELECTED PUBLICATIONS: