B-159. Intravenous Shiga toxin 2 Promotes Enteritis and Renal Injury Characterized by Polymorphonuclear Leukocyte Infiltration and Thrombosis in Dutch Belted Rabbits

A. Garcia1, R. P. Marini1, J. L. Catalfamo2, K. A. Knox1, D. B. Schauer1, A. B. Rogers1, J. G. Fox1;
1Massachusetts Inst. of Technology, Cambridge, MA, 2Cornell Univ., Ithaca, NY.

Enterohemorrhagic Escherichia coli (EHEC) infection may be clinically manifested by hemolytic uremic syndrome, a leading cause of acute renal failure in children. Dutch Belted (DB) rabbits are susceptible to EHEC-induced disease. Using real-time quantitative RT-PCR we measured the renal mRNA expression of cytokines and fibrinolytic factors in DB rabbits challenged with intravenous Stx2. Twelve 6-week-old DB rabbits were divided into two experimental groups and one control group (4 rabbits per group; 2 males and 2 females). Experimental groups (Groups 1 and 2) were intravenously infused with Stx2 and the control group was intravenously infused with sterile saline solution. Group 1 rabbits received an incremental dose totaling 1200 ng/kg of Stx2 during an 8-day period whereas Group 2 rabbits received a single dose (1200 ng/kg) of Stx2. Group 1 rabbits developed mild disease. In contrast, Group 2 rabbits developed severe diarrhea, higher levels of circulating polymorphonuclear leukocytes, increased mean platelet volume, and increased fibrinogen levels. Group 2 rabbits developed polymorphonuclear leukocyte infiltration in the intestine and kidney as well as glomerular congestion, luminal constriction, and mesangial deposits. These renal lesions were associated with significant up-regulation of interleukin-8 (P<0.006), plasminogen activator inhibitor-1 (P<0.04), and tissue plasminogen activator (P=0.05). Circulating Stx2 promoted dose-dependent enteritis and renal injury characterized by inflammation and impaired fibrinolysis leading to thrombosis.