Pathogenic functions and diagnostic utility of cytokines/chemokines in EHEC‐HUS

Abstract

Hemolytic − uremic syndrome (HUS) is a severe complication of infection by Shiga toxin (STx)‐producing enterohemorrhagic Escherichia coli. Hemolytic − uremic syndrome is defined clinically as a triad of non‐immune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injuries. Neurologic complications such as acute encephalopathy are also observed. In humans, endothelial cells, proximal tubular epithelial cells, mesangial cells, podocytes, intestinal epithelial cells, and monocytes / macrophages are susceptible to STx‐mediated injury. Shiga toxin induces the secretion of inflammatory cytokines and chemokines from susceptible cells, including tumor necrosis factor‐α interleukin (IL)‐1, IL‐6, and IL‐8. These cytokines and chemokines contribute to the pathogenesis of HUS and encephalopathy by enhancing STx‐induced cytotoxicity and inducing inflammatory cell infiltration. Serum cytokine/chemokine levels are therefore useful as indicators of disease activity and predictors of progression from acute kidney injury to chronic kidney disease. Anti‐inflammation therapy combined with apheresis to remove excessive cytokines / chemokines and methylprednisolone pulse therapy to suppress cytokine/chemokine production may be an effective treatment regimen for severe E. coli‐associated HUS. However, this regimen requires careful monitoring of potential side effects, such as infections, thrombus formation, and hypertension.

Shiga Toxin (Stx)-Binding Glycosphingolipids of Primary Human Renal Cortical Epithelial Cells (pHRCEpiCs) and Stx-Mediated Cytotoxicity

“…More precisely, glomerular endothelial cells in the kidney and microvascular endothelial cells in the brain are preferably targeted by Stx leading to acute renal impairment and cerebral disturbances resulting in severe extraintestinal complications of STEC infections [12,13,38,45,50,125,126]. Because the renal epithelium may also be involved in the pathogenesis of Stx-mediated HUS, in vitro studies using primary kidney-derived epithelial cells have become increasingly recognized [13,46,127,128]. Besides the reported sensitivity of Stx to immortal epithelial cell lines of renal origin (not further discussed here), few studies have been performed so far, which provided essential knowledge on Stx-mediated damage of cultured primary human tubular [51,66,67,[70][71][72][129][130][131] and glomerular epithelial cells [68,69].…”

“…Thus, Stxmediated toxicity towards erythroblasts during the course of erythropoiesis might contribute to anemia observed during manifestation of STEC-HUS. Moreover, renal proximal tubular epithelial cells, mesangial cells, and podocytes, as well as intestinal epithelial cells and monocytes/macrophages, are susceptible to Stx-mediated injury in humans [41][42][43][44][45][46]. However, human kidney and brain microvascular endothelial cells are widely used to explore the impact of Stx-mediated cellular dysfunction because of the association of endothelial injury in the kidney with HUS and due to neurological impairment of the brain being the most frequent cause of acute mortality in patients with STEC-HUS [38,[47][48][49][50].…”

Diagnosis of Chikungunya Virus in Febrile Patients From a Malaria Holoendemic Area

“…Even though cytokines are produced by the body in response to microbial invasion as a defense strategy, uncontrolled inflammation triggered by cytokines (pro-inflammatory cytokines) such as TNF-α, IFN-γ, IL-16, IL-12, promotes severity of infection, organ failure and mortality (Shimizu 2020;Schernthaneret al,2017;Teoet al, 2018;Ragabet al,2020). In contrast, anti-inflammatory cytokines such as IL-10, IL-4, and IL-13 attenuate proinflammatory cytokines, preventing the severity of infection and organ failure (Wojdasiewiczet al, 2014;Venugopalanet al, 2014;Teoet al, 2018).…”

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

“…There is an increasing body of evidence that Stx may directly attack not only renal and cerebral endothelial cells leading to pathological malfunction of the endothelium that faces Stx-loaded granulocytes and/or Stx-carrying microvesicles. In terms of the kidney, Stx also damages other renal cells videlicet glomerular and tubular epithelial cells as well as mesangial cells [ 136 , 140 , 390 , 417 , 418 ]. To briefly explain these different cell types of the Bowman capsule, glomerular epithelial cells surround the glomerular capillary tuft as an envelope would, while tubular epithelial cells line the renal tubuli being connected with the renal capsule wall, and mesangial cells constitute the central stalk of the glomerulus [ 419 , 420 ].…”