SHIGA TOXIN MODE OF ACTION IN E. COLI O157:H7 DISEASE

Tom G. Obrig

Department of Microbiology and Immunology, University of Rochester, Box 672, 601 Elmwood Avenue, Rochester, NY 14642

Received 12/2/97 Accepted 12/8/97

8. SENSITIVITY OF HUMAN ENDOTHELIAL CELLS TO Stxs

8.1 Endothelial cells are the putative target of Stxs

It has been 10 years since the first report indicating that Stx was cytotoxic to endothelial cells (52). Those studies were prompted by previous reports that endothelial cells were the site of initial damage in HUS (25,53,54). Histopathologic examination of kidney samples from HUS patients revealed glomerular vascular capillaries with swollen endothelial cells (53,55). In this study, microvascular angiopathy was present in all patients diagnosed with HUS and having an infection with Stx-producing E. coli. The authors concluded that endothelial cells are the putative primary target cells of Stx. Others have demonstrated that human kidney contains the Gb₃ receptor for Shiga toxin, particularly in young children (31). Endothelial cells isolated from human kidney also express Gb3 and are very sensitive to Shiga toxin (24).

Although glomerular endothelial cells appears to represent the primary target of the Stxs, more evidence is accumulating, both direct and indirect, that endothelial cells from other vascular beds are also subject to Stx damage. It is now certain that microvascular (vs. large vessel) endothelial cells from a number of locations are very sensitive to the Stxs. This would explain the nature of hemorrhagic colitis, and changes in some other organs (e.g. pancreas, lung), and why neurological complications occur in over 30 to 50% of HUS patients. These may all be due to the preference of Stxs to recognize microvascular endothelial cells.

New evidence shows that Stxs can directly interact with vascular cell types other than endothelial cells in a way that may be important to HUS (9,56,57). In an earlier report, it was suggested that Stx interacts directly with macrophage to elicit cytokines (56). Indeed, this has now been demonstrated directly by murine macrophage responding to Stx1 with increased IL-1 and IL-6 production (46). Although macrophage are considerably less sensitive to Stx, these data are relevant and point out that release of cytokines from macrophage would add to the validity of the hypothesis described below that Stx action on the endothelium is enhanced by cytokines in developing HUS (58,59,60,61).

8.2 Host cytokine regulation of Stx-sensitivity in endothelial cells

To date, all evidence suggests that Stxs combine with other bacterial and host factors to cause HUS. Workers in this field tend to agree that induction of cytokines by LPS and Stx in macrophage does take place and this may be more localized to the kidney (46,62,63). As stated above, Stx interacts directly with other cell types such as macrophage to elicit cytokines and adherence molecules. Cytokines may act alone or in combination to directly alter the physiological state of endothelial cells. Firstly, these factors tilt the endothelial hemostatic balance towards a more procoagulant/antifibrinolytic state (62,64,65,66,67,68) which is a hallmark of HUS. Secondly, LPS and some cytokines induce Gb3 on endothelial cells (24,59,69), through a series of signal-transduction steps involving protein kinase C (70,71). The author views EHEC-associated HUS as a gram negative bacterial response which has been diverted by Stx. Future research should reveal the signal transduction pathways activated during induction of Gb3 by LPS, cytokines, and other agents. The more difficult task will be to determine the individual events that take place in humans during development of Stx-associated HUS. This is particularly true in the absence of a reproducible animal model for this disease.