David O. Beenhouwer, MD
Assistant Professor of Medicine in Residence, UCLA School of Medicine
Staff Internist & 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.

SELECTED PUBLICATIONS:

Rocha MA, Lai CW, Vasuthasawat A, Penichet ML, Beenhouwer DO. 2008. Enhanced humoral and cellular immune responses against Cryptococcus neoformans using antibody-(IL-2) or -(GM-CSF) fusion proteins specific for the capsular polysaccharide. [submitted]

Schwartzman WA, Beenhouwer DO, Schaberg DR. 2007. How relevant were the models used to measure the impact of Panton-Valentine leukocidin in human staphylococcal infections? J Infect Dis. 195:1726-7

Beenhouwer DO, Yoo EM, Lai CW, Rocha MA, Morrison SL. 2007. Human immunoglobulin G2 (IgG2) and IgG4 but not IgG1 or IgG3 protect mice against Cryptococcus neoformans Infection. Infect Immun. 75:1424-35

Furst DE, Wallis R, Broder M, Beenhouwer DO. 2006. Tumor Necrosis Factor Antagonists: Different Kinetics and/or Mechanisms of Action May Explain Differences in the Risk for Developing Granulomatous Infection. Semin Arthritis Rheum. 36:159-67

Zhu L, van de Lavoir MC, Albanese J, Beenhouwer DO et al. 2005. Production of human monoclonal antibody in eggs of chimeric chickens. Nat Biotechnol. 23:1159-69.

Beenhouwer D, Wallis R, Broder M, Furst DE. 2004. Mechanisms of action of tumor necrosis factor antagonist and granulomatous infections. J Rheumatol. 31:1888-92.

Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. 2004. Clin Infect Dis. 38:1261-5.

May RJ, Beenhouwer DO, Scharff MD. 2003. Antibodies to keyhole limpet hemocyanin cross-react with an epitope on the polysaccharide capsule of Cryptococcus neoformans and other carbohydrates: implications for vaccine development. Journal of Immunology. 171:4905-12.

Beenhouwer DO, May RJ, Valadon P, Scharff MD. 2002. High affinity mimotope of the polysaccharide capsule of Cryptococcus neoformans identified from an evolutionary phage peptide library. Journal of Immunology. 169:6992-9.

Shapiro S, Beenhouwer DO, Feldmesser M, Taborda C, Carroll MC, Casadevall A, Scharff MD. 2002. Immunoglobulin G monoclonal antibodies to Cryptococcus neoformans protect mice deficient in complement component C3. Infection and Immunity. 70:2598-604.

Beenhouwer DO, Shapiro S, Feldmesser M, Casadevall A, Scharff MD. 2001. Both Th1 and Th2 cytokines affect the ability of monoclonal antibodies to protect mice against Cryptococcus neoformans. Infection and Immunity. 69:6445-55.

Beenhouwer DO, Valadon P, May R, Scharff MD. 2000. Peptide mimicry of the polysaccharide capsule of Cryptococcus neoformans. In Molecular Mimicry, MW Cunningham and RS Fujinami (eds.), ASM Press, Washington, DC.

Beenhouwer DO, KC Chintalacharuvu, SL Morrison. 2004. Immunoglobulin synthesis and secretion. In Monoclonal Gammopathies and the Kidney.

 

2008