Erik  L.  Hewlett
Degree(s): MD
Graduate School: Johns Hopkins, School of Medicine
Primary Appointment: Professor, Medicine, Infectious Diseases and International Health
Research Interests:
Structure and Function of Bacterial Toxins: Roles in Microbial Pathogenesis and Uses in Biomedical Research
Email Address: eh2v@virginia.edu
Biomedical Sciences Graduate Program(s)
  • Biomedical Sciences Graduate Programs
    • Research Description

    Bordetella pertussis, the bacterium which causes pertussis or whooping cough, produces several protein toxins which modifiy the functions of host cells. The two of these which are the focus of our research are: a) adenylate cyclase toxin (ACT) and b) pertussis toxin (PT). Both are key virulence factors in the disease of pertussis, protective antigens in eliciting immunity in animal models and toxins with novel effects on target cells. ACT is a 177kd protein possessing a calmodulin-activated adenylate cyclase enzymatic domain which is delivered to the cytosol of target cells, resulting in supraphysiologic cyclic AMP levels. The toxin must be acylated and bind multiple calcium atoms in order to be active. In the course of its interaction with target cells, it creates a transmembrane pore which allows efflux of intracellular K+ and for some erythrocytes, it is hemolytic. Current work is directed at defining the structure of ACT and the effect of acylation and the calcium-induced conformational change on toxin activities. The nature of ACT's interaction with the bacterial outer membrane including its membrane associated proteins, and the process by which the toxin is transferred to the host cell are focal points in a new direction of this research. ACT localization on the surface of the producing organism, B. pertussis, and its delivery to target cells from that site is a project leading to greater emphasis on the toxin's role in pathogenesis of pertussis. PT is a heteropentamer and a member of the family of ADP-ribosylation protein toxins. Its target molecules are some of the heterotrimeric G proteins such as Gi and Gt', and the result of their modification by PT is inhibition of G protein-mediated signal transduction. Despite its clear importance in clinical pertussis, the target tissue for PT in the disease process is unknown, thus impairing understanding of disease pathophysiology. Current studies include cellular effects of PT in vitro and in vivo, and evaluation of its consequences in patients with pertussis.

    Selected Publications
  • 1: Zaretzky FR, Gray MC, Hewlett EL. Mechanism of association of adenylate cyclase toxin with the surface of Bordetella pertussis: a role for toxin-filamentous haemagglutinin interaction. Mol Microbiol. 2002 Sep;45(6):1589-98.
  • Gao Z, Young RA, Trucco MM, Greene SR, Hewlett EL, Matschinsky FM, Wolf BA. Protein kinase A translocation and insulin secretion in pancreatic beta-cells: studies with adenylate cyclase toxin from Bordetella pertussis. Biochem J. 2002 Dec 1;368(Pt 2):397-404. Erratum in: Biochem J. 2003 Feb 1;369(Pt 3):739.
  • Rhodes CR, Gray MC, Watson JM, Muratore TL, Kim SB, Hewlett EL, Grisham CM. Structural consequences of divalent metal binding by the adenylyl cyclase toxin of Bordetella pertussis.Arch Biochem Biophys. 2001 Nov 15;395(2):169-76.
  • Gray MC, Lee SJ, Gray LS, Zaretzky FR, Otero AS, Szabo G, Hewlett EL.Translocation-specific conformation of adenylate cyclase toxin from Bordetella pertussis inhibits toxin-mediated hemolysis. J Bacteriol. 2001 Oct;183(20):5904-10.
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      Office Address: Box 800419 MR-6, 345 Crispell Dr Room 1526, 
      Office Phone: +1 434-243-7088, +1 434-924-5945
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