Erik L. Hewlett, MD
Erik L. Hewlett
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.
Chavali AK, D'Auria KM, Hewlett EL, Pearson RD, Papin JA. A metabolic network approach for the identification and prioritization of antimicrobial drug targets. Trends Microbiol. 2012 Mar;20(3):113-23. doi: 10.1016/j.tim.2011.12.004. Epub 2012 Jan 31. Review.
Donato GM, Goldsmith CS, Paddock CD, Eby JC, Gray MC, Hewlett EL. Delivery of Bordetella pertussis adenylate cyclase toxin to target cells via outer membrane vesicles. FEBS Lett. 2012 Feb 17;586(4):459-65. doi: 10.1016/j.febslet.2012.01.032. Epub 2012 Jan 28.
D'Auria KM, Donato GM, Gray MC, Kolling GL, Warren CA, Cave LM, Solga MD, Lannigan JA, Papin JA, Hewlett EL. Systems analysis of the transcriptional response of human ileocecal epithelial cells to Clostridium difficile toxins and effects on cell cycle control. BMC Syst Biol. 2012 Jan 6;6:2. doi: 10.1186/1752-0509-6-2.
Eby JC, Gray MC, Mangan AR, Donato GM, Hewlett EL. Role of CD11b/CD18 in the process of intoxication by the adenylate cyclase toxin of Bordetella pertussis. Infect Immun. 2012 Feb;80(2):850-9. doi: 10.1128/IAI.05979-11. Epub 2011 Dec 5.
Gray MC, Hewlett EL. Cell cycle arrest induced by the bacterial adenylate cyclase toxins from Bacillus anthracis and Bordetella pertussis. Cell Microbiol. 2011 Jan;13(1):123-34. doi: 10.1111/j.1462-5822.2010.01525.x. Epub 2010 Oct 14.
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