Cytokines expression from altered motor thalamus and behavior deficits following sublethal administration of Shiga toxin 2a involve the induction of the globotriaosylceramide receptor.

Encephalopathy associated with hemolytic uremic syndrome is produced by enterohemorrhagic E. coli (EHEC) infection, which releases the virulence factors Shiga toxin (Stx) and lipopolysaccharide (LPS). Neurological compromise is a poor prognosis and mortality factor of the disease, and the thalamus is one of the brain areas most frequently affected. We have previously demonstrated the effectiveness of anti-inflammatory drugs to ameliorate the deleterious effects of these toxins. However, the thalamic production of cytokines involved in pro-inflammatory processes has not yet been acknowledged. The aim of this work attempts to determine whether systemic sublethal Stx2a or co-administration of Stx2a with LPS are able to rise a proinflammatory profile accompanying alterations of the neurovascular unit in anterior and lateral ventral nuclei of the thalamus (VA-VL) and motor behavior in mice. After 4 days of treatment, Stx2a affected the lectin-bound microvasculature distribution while increasing the expression of GFAP in reactive astrocytes and producing aberrant NeuN distribution in degenerative neurons. In addition, increased swimming latency was observed in a motor behavioral test. All these alterations were heightened when Stx2a was co-administered with LPS. The expression of pro-inflammatory cytokines TNFα, INF-γ and IL-2 was detected in VA-VL. All these effects were concomitant with increased expression of the Stx receptor globotriaosylceramide (Gb3), which hints at receptor involvement in the neuroinflammatory process as a key finding of this study. In conclusion, Stx2a to Gb3 may be determinant in triggering a neuroinflammatory event, which may resemble clinical outcomes and should thus be considered in the development of preventive strategies.

Anti-inflammatory agents reduce microglial response, demyelinating process and neuronal toxin uptake in a model of encephalopathy produced by Shiga Toxin 2.

Infections by Enterohemorrhagic Escherichia coli may cause in addition to hemolytic uremic syndrome neurological disorders which may lead to fatal outcomes in patients. The brain striatum is usually affected during this outcome. The aim of this study was to determine in this area the role of the microglia in pro-inflammatory events that may occur during Shiga toxin 2 intoxication and consequently to this, whether oligodendrocytes were being affected. In the present paper we demonstrated that anti-inflammatory treatments reduced deleterious effects in brain striatal cells exposed to Shiga toxin 2 and LPS. While dexamethasone treatment decreased microglial activation and recovered myelin integrity in the mice striatum, etanercept treatment decreased neuronal uptake of Stx2 in rat striatal neurons, improving the affected area from toxin-derived injury. In conclusion, microglial activation is related to pro-inflammatory events that may deteriorate the brain function during intoxication with Stx2 and LPS. Consequently, the role of anti-inflammatory agents in the treatment of EHEC-derived encephalopathy should be studied in clinical trials.