Tolerance to lipopolysaccharide (LPS) regulates the endotoxin effects on Shiga toxin-2 lethality

It has been suggested that Shiga toxin (Stx) is necessary but not sufficient for hemolytic uremic syndrome (HUS) development, and pro-inflammatory stimuli such as lipopolysaccharide (LPS) from Gram negative bacteria are needed. Taking into account that LPS is present in the natural infection during HUS development, detoxification or regulation of LPS activity could be crucial to define the course of the disease. The objective of the present study was to investigate whether tolerance to LPS and/or antibodies to LPS, are able to modify the LPS-induced modulation of Stx type-2 (Stx2) lethality in a mouse model. Our results demonstrate that the high levels of IgG anti-LPS antibodies in immunized mice did not modify the dual effects of LPS (enhancement or protection) on Stx2 action. This could be attributed to the fact that antibodies do not recognize the active portion of LPS molecule (lipid A). However, the enhancement of Stx2 toxicity exerted by LPS was inhibited in tolerant mice. This effect could be ascribed to the inhibition of LPS-induced TNF-alpha and IL-1beta secretion in tolerant animals, two cytokines known to be involved in the overexpression of Stx receptors. The phenomenon of LPS-induced protection on Stx2 toxicity was also inhibited in tolerant animals, although the mechanism involved in this effect is not clear. This is the first description which shows the influence of endotoxin tolerance on the evolution of experimental HUS. However, like in Gram negative infections, further knowledge on tolerance mechanism is necessary in order to achieve a comprehensive view of this phenomenon.