The Staphylococcus aureus Alpha-Toxin Perturbs the Barrier Function in Caco-2 Epithelial Cell Monolayers by Altering Junctional Integrity

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Increased microvascular permeability is a hallmark of sepsis and septic shock. Intestinal mucosal dysfunction may allow translocation of bacteria and their products, thereby promoting sepsis and inflammation. Although<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Staphylococcus aureus</jats:named-content>alpha-toxin significantly contributes to sepsis and perturbs the endothelial barrier function, little is known about possible effects of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>alpha-toxin on human epithelial barrier functions. We hypothesize that<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>alpha-toxin in the blood can impair the intestinal epithelial barrier and thereby facilitate the translocation of luminal bacteria into the blood, which may in turn aggravate a septic condition. Here, we showed that staphylococcal alpha-toxin disrupts the barrier integrity of human intestinal epithelial Caco-2 cells as evidenced by decreased transepithelial electrical resistance (TER) and reduced cellular levels of junctional proteins, such as ZO-1, ZO-3, and E-cadherin. The Caco-2 cells also responded to alpha-toxin with an elevated cytosolic calcium ion concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>), elicited primarily by calcium influx from the extracellular environment, as well as with a significant reduction in TER, which was modulated by intracellular calcium chelation. Moreover, a significantly larger reduction in TER and amounts of the junctional proteins,<jats:italic>viz</jats:italic>., ZO-3 and occludin, was achieved by basolateral than by apical application of the alpha-toxin. These experimental findings thus support the hypothesis that free staphylococcal alpha-toxin in the bloodstream may cause intestinal epithelial barrier dysfunction and further aggravate the septic condition by promoting the release of intestinal bacteria into the underlying tissues and the blood.</jats:p>

Staphylococcus aureusα-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells

“…As previously shown in different cell types (34,50) including airway epithelial cells (14,43), [Ca 2ϩ ] i increases upon exposure of cells to Hla. These observations were confirmed in this study.…”

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure

“…The saline control group was enriched for Bifidobacteriaceae, a well-known beneficial bacterial family (Figure 6F and Supplementary Figure S2) [43]. In contrast, the Ang II group had different enriched taxa, such as Staphylococcaceae, which can impair gut barrier functions [44,45]. These data demonstrate that Ang II-HTN mice have taxonomically distinct microbiota.…”

Development of an in vitro colonization model to investigateStaphylococcus aureusinteractions with airway epithelia

“…S . aureus alpha‐toxin is known to alter tight junction integrity by interfering with processing of E‐cadherin (Inoshima et al ., ; Kwak et al ., ), which could be the reason for the rapid loss of transepithelial resistance.…”

“…known to alter tight junction integrity by interfering with processing of E-cadherin (Inoshima et al, 2011;Kwak et al, 2012), which could be the reason for the rapid loss of transepithelial resistance. Our observations with CC30 strains coincide with findings on S. aureus production of alpha-toxin (Deleo et al, 2011).…”