Infectious
Disease Research & Teaching at
the Veterans Affairs Medical Center
Wade
Park, Cleveland, Ohio
The focus of research at the VA centers on
the problems of antimicrobial resistance, bacterial pathogenesis, and
mycobacteriology. This comprehensive program takes place at the Research
Service of the Veterans Affairs Medical Center, Case Western Reserve
University School of Medicine, and the Biomedical Research Building .
Programs involve understanding the molecular genetics of ampicillin and
vancomycin resistance in enterococci, the molecular epidemiolgy of
vancomycin resistant enterococci and the relationship to antibiotic use,
b-lactamase mediated resistance, host-pathogen interactions in
mycobacteria and HIV infection, and prokaryotic cell-cell signaling.
Dr. Louis B. Rice. Chief of Medicine,
Veterans Affairs Medical Center, Professor of Medicine, Case Western
Reserve University, and member of the Infectious Diseases Section. The
primary research interests of Dr. Rice involves understanding the
molecular genetics of ampicillin and vancomycin resistance in Enterococcus
faecium. His laboratory is dedicated to the characterization of mobile
genetic elements in enterococci. Recent work centers upon determining the
regulation and expression of resistant penicillin binding protein 5 (PBP5)
in E. faecium. Other projects include: a) characterization of novel
extended spectrum b-lactamase genes in Klebsiella pneumoniae and other
enteric bacilli; b) testing the efficacy of antimicrobial agents in animal
models of infection ; c) characterization of clinical isolates of
methicillin resistant staphylococci.
Dr. Zara Toossi. Professor of Medicine Case
Western Reserve University. Attending Physician, Infectious Disease
Section, Veterans Affairs Medical Center. Dr. Toosi laboratory is
interested in the host responses to mycobacteria. The laboratory studies
the immunosuppressive effects of TGF-b, the interaction of cytokines and
their net balance with regard to macrophage activation (or deactivation)
and immune stimulation (or suppression). Her laboratory seeks to
understand how these factors ultimately determine the success of
host-immune response against tuberculosis . The lab investigates the
interaction of transforming growth factor beta1 (TGF-b 1) and
interleukin-10 (IL-10) in purified protein derivative (PPD)-stimulated
human HIV infected mononuclear cell cultures in vitro.
Dr. Philip N. Rather. Associate Professor
of Medicine Case Western Reserve University , member of the Division of
Infectious Diseases and Molecular Biology and Microbiology. Dr. Rather
studies the control of bacterial gene
expression by cell-to-cell communication
with extracellular factors. His lab is interested in the mechanisms of
cell to cell signaling (quorum sensing) in bacteria. Bacteria produce
small chemical signals (pheromones or autoinducers) which regulate gene
expression when they reach a critical concentration. The role of quorum
sensing in regulation of a chromosomal 2'-N-acetyltransferase [aac(2')] in
Providencia stuartii is one area of focus. His lab uses genetic approaches
to dissect the regulatory pathways which control aac(2') expression. One
pathway involves response to a small peptide signal, AR-factor, which
represses aac(2') transcription. A second pathway involves regulation of
mRNA stability. Another area of interest in the physiological role of
quorum sensing in E. coli. A number of quorumsensing regulated genes have
been identified and they appear to have a common role in amino acid cat
abolism.
Dr. Curtis Donskey. Chief, Infection
Control. Assistant Professor of Medicine, Case Western Reserve University.
Attending Physician, Infectious Disease Section, Veterans Affairs Medical
Center. Dr. Donskey's laboratory is interested in the molecular
epidemiology of vancomycin-resistant enterococci (VRE). To this end his
laboratory has established a mouse model of vancomycin-resistant
Enterococcus faecium (VRE) intestinal colonization. This model is used to
study the effect of different antibiotics on persistence and density of
VRE colonization. His laboratory uses denaturing gradient gel
electrophoresis to study the molecular epidemiolgy of pathogens that are
difficult to isolate and culture. He is also developing a continuous flow
culture system to investigate the interactions of intestinal pathogens in
a dynamic system.
Dr. Richard Graham. Professor of Medicine,
Case Western Reserve University. Attending Physician, Infectious Disease
Section, Veterans Affairs Medical Center. Dr. Graham's academic interests
include the clincal care of HIV infected patients. Major emphasis is also
placed on teaching clinical infectious diseases syndromes.
Dr. Robert A. Bonomo. Section Chief,
Veterans Affairs Medical Center. Dr. Bonomo's laboratory is dedicated to
the study of structure function relationships in the class A b-lactamase,
SHV. This chromosomal and plasmid encoded b-lactamase is usually found in
Klebsiella pneumonia and confers high level resistance to third generation
cephalosporins (cefotaxime, ceftazidime) and aztreonam. This resistance
can render ineffective the most frequently used drugs to treat serious
nosocomial infections. Our goals are to understand what amino acid
substitutions permit evolution of novel substrate profiles and what
factors control expression of these periplasmic enzymes. By using site
directed mutagenesis and immunological tools to quantify expression, we
are able to draw conclusions as to why these highly resistant variants may
have arisen in nature. We are also interested in quantifying b-lactamase
expression in organisms harboring Class C b-lactamases. We have developed
antibodies able to detect the presence of this class of enzymes in
clinical strains, thereby facilitating molecular epidemiological
investigations
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