ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN GNOTOBIOTIC MICE INFECTED WITHAN ESCHERICHIA-COLI O157-H7 STRAIN

Gnotobiotic mice inoculated with an enterohemorrhagic Escherichia coli (EHEC) 0157:H7 strain developed a flaccid paresis, usually culminatin g in death. The bacteria colonized feces at 10(9) to 10(10) CFU per g (inoculum size: 2.0 x 10(9) CFU/mouse), and Shiga-like toxins (SLTs) w ere detected in the feces, A microscopic examination of colons showed mild inflammatory cell infiltration, thinning of the intestinal wall, or necrotic foci. Necrosis of tubular cells was noted in these symptom atic mice, Microhemorrhage, thrombosis, and edematous changes of the b rain were also seen, Inflammatory cytokines, tumor necrosis factor alp ha (TNF-alpha), interleukin 1 alpha (IL-1 alpha), and IL-6, were detec ted in the kidney after EHEC infection, but not in the serum, In the b rain, only TNF-or was detected, When 2.0 x 10(2) CFU of EHEC 0157:H7 w as fed to germ-free mice, the number of bacteria began to rise rapidly on day I and was maintained at 10(8) to 10(9) CFU/g of feces, SLTs me re detected in the feces of the mice, However, the mice showed no hist ological changes and no cytokine responses, similar to what was found for controls, Treatment with TNF-alpha modified the clinical neural si gns, histopathological changes, and cytokine responses; mice treated,v ith TNF-alpha developed severe neurotoxic symptoms and had higher freq uencies of systemic symptoms and glomerular pathology, Strong cytokine responses were seen in the kidney and brain, Serum cytokines were als o detected in this group. In contrast, a TNF-alpha inhibitor (protease inhibitor) inhibited these responses, especially in the brain, Howeve r, local synthesis of the cytokines was observed in the kidney, Thus, TNF-or and the other proinflammatory cytokines could be important in m odifying the disease caused by EHEC.