Upregulation of Shiga Toxin Receptor CD77/Gb3 and Interleukin‐1β Expression in the Brain of EHEC Patients with Hemolytic Uremic Syndrome and Neurologic Symptoms

Abstract

In 2011, a large outbreak of Shiga toxin-producing enterohemorrhagic Escherichia coli (EHEC) infections occurred in northern Germany, which mainly affected adults. Out of 3842 patients, 104 experienced a complicated course comprising hemolytic uremic syndrome and neurological complications, including cognitive impairment, aphasia, seizures and coma. T2 hyperintensities on magnet resonance imaging (MRI) bilateral in the thalami and in the dorsal pons were found suggestive of a metabolic toxic effect. Five of the 104 patients died because of toxic heart failure. In the present study, the post-mortem neuropathological findings of the five EHEC patients are described. Histological investigation of 13 brain regions (frontal, temporal, occipital cortex, corpora mammillaria, thalamus, frontal operculum, corona radiata, gyrus angularis, pons, medulla oblongata, cerebellar vermis and cerebellar hemisphere) showed no thrombosis, ischemic changes or fresh infarctions. Further, no changes were found in electron microscopy. In comparison with five age-matched controls, slightly increased activation of microglia and a higher neuronal expression of interleukin-1β and of Shiga toxin receptor CD77/globotriaosylceramide 3 was observed. The findings were confirmed by Western blot analyses. It is suggested that CD77/globotriaosylceramide upregulation may be a consequence to Shiga toxin exposure, whereas increased interleukin-1β expression may point to activation of inflammatory cascades.

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS)

“…Some evidence suggests that neurological complications could be more related to systemic and local inflammatory reactions than to thrombosis, ischemic changes or direct toxic effect of Stx on neurons. In this regard, the postmortem neuropathological investigation of brains from five patients who died during the German outbreak in 2011 showed a slightly increased activation of microglia and a higher neuronal expression of IL-1β and Gb3 [119]. In the same line of reasoning, elevated serum levels of tau protein are seen in patients with STEC encephalopathy compared with STEC O111/ HUS patients without encephalopathy, patients with non-STEC-related acute encephalopathy and healthy controls [120].…”

Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta‐mediated neurotoxicity

“…Detection of activated caspase 3 was performed using anti human/mouse active caspase 3 antibody AF835 (1 : 500 in blocking buffer; R & D Systems, Minneapolis, MN, USA), followed by detection with an Alexa488 labeled secondary anti‐rabbit antibody (Hagel et al . ). Slides were analyzed by fluorescence microscopy with a Zeiss Axio microscope (Zeiss, Oberkochen, Germany) and pictures were recorded with a Zeiss AxioCam MRm and the AxioVision V 4.8.2.0 software (Zeiss, Oberkochen, Germany) at a magnification of 10×.…”

Shiga Toxins as Multi-Functional Proteins: Induction of Host Cellular Stress Responses, Role in Pathogenesis and Therapeutic Applications

“…In human brain microvascular endothelial cells (HBMEC) and human brain endothelial cells (HBEC), pretreatment with TNF-α and IL-1β as inflammatory stimuli markedly increased the toxicity of Stxs by enhancing the expression of the toxin receptor Gb 3 on these cells in comparison with the untreated cells, suggesting the role of proinflammatory cytokines in sensitizing brain cells to the toxins [ 145 , 146 , 167 ]. In the 2011 outbreaks of Shiga toxin-producing EHEC infections in Germany, these findings were confirmed in the brain of infected patients with HUS and neurological complications as a consequence of systemic inflammatory cascades activated by upregulating CD77/Gb 3 neuronal expression [ 168 ]. Importantly, a rabbit model treated with purified Stx2 showed that neuroinflammatory responses, such as increased expression of TNF-α or IL-1β in the CNS parenchyma and microglial activation at an early stage, may lead to occasional apoptotic neurons as the onset of neurological symptoms later in the disease [ 126 ].…”