Abstract
Shiga toxin (Stx) produced by enterohemorrhagic E. coli produces hemolytic uremic syndrome and encephalopathies in patients, which can lead to either reversible or permanent neurological abnormalities, or even fatal cases depending on the degree of intoxication. It has been observed that the inflammatory component plays a decisive role in the severity of the disease. Therefore, the objective of this work was to evaluate the behavior of microglial cell primary cultures upon Stx2 exposure and heat shock or lipopolysaccharide challenges, as cues which modulate cellular environments, mimicking fever and inflammation states, respectively. In these contexts, activated microglial cells incorporated Stx2, increased their metabolism, phagocytic capacity, and pro-inflammatory profile. Stx2 uptake was associated to receptor globotriaosylceramide (Gb3)-pathway. Gb3 had three clearly distinguishable distribution patterns which varied according to different contexts. In addition, toxin uptake exhibited both a Gb3-dependent and a Gb3-independent binding depending on those contexts. Altogether, these results suggest a fundamental role for microglial cells in pro-inflammatory processes in encephalopathies due to Stx2 intoxication and highlight the impact of environmental cues.
Highlights
Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, and hemolytic uremic syndrome (HUS) once the toxin enters circulation from the gut (Karmali, 2004)
Upon the detection of a variety of Cell Behavior Upon Stx2 (CNS) dysfunctions, MG cells undergo a complex, multistage activation process that converts them into an activated status (Kettenmann et al, 2011)
Pathogenesis of CNS during the acute phase of HUS is known to correlate with brain-blood-barrier disruption, neuronal disturbances and astrogliosis (Pinto et al, 2017), less is known so far about MG cell behavior and their role in the events observed in these CNS complications
Summary
Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, and hemolytic uremic syndrome (HUS) once the toxin enters circulation from the gut (Karmali, 2004). HUS is an orally acquired infective illness produced by the ingestion of contaminated food, water and/or cross infection, and includes thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure (Gianantonio et al, 1973). The endemic variant that predominates in Argentina, is a protein formed by a catalytic subunit A (StxA) and five subunits B (StxB) related with toxin binding. StxA possesses N-glycosidase activity and inhibits protein biosynthesis. To perform this task it must be transported to the cytosol by StxB (Johannes and Decaudin, 2005; Sandvig and van Deurs, 2005) through its receptor, located in the cell membrane. Gb3 may serve as a precursor for the synthesis of more complex globoseries glycosphingolipids, such as globotetraosylceramide (Gb4) (Kavaliauskiene et al, 2017)
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