Abstract
Transgenic C57BL/6 mice expressing human serum amyloid P component (HuSAP) are resistant to Shiga toxin 2 (Stx2) at dosages that are lethal in HuSAP-negative wild-type mice. However, it is well established that Stx2 initiates extra-intestinal complications such as the haemolytic-uremic syndrome despite the presence of HuSAP in human sera. We now demonstrate that co-administering purified Escherichia coli O55 lipopolysaccharide (LPS), at a dosage of 300 ng/g body weight, to HuSAP-transgenic mice increases their susceptibility to the lethal effects of Stx2. The enhanced susceptibility to Stx2 correlated with an increased expression of genes encoding the pro-inflammatory cytokine TNFα and chemokines of the CXC and CC families in the kidneys of LPS-treated mice, 48 hours after the Stx2/LPS challenge. Co-administering the glucocorticoid dexamethasone, but not the LPS neutralizing cationic peptide LL-37, protected LPS-sensitized HuSAP-transgenic mice from lethal doses of Stx2. Dexamethasone protection was specifically associated with decreased expression of the same inflammatory mediators (CXC and CC-type chemokines and TNFα) linked to enhanced susceptibility caused by LPS. The studies reveal further details about the complex cascade of host-related events that are initiated by Stx2 as well as establish a new animal model system in which to investigate strategies for diminishing serious Stx2-mediated complications in humans infected with enterohemorrhagic E. coli strains.
Highlights
Haemolytic-uremic syndrome (HUS) is characterized by a triad of clinical signs including thrombocytopenia, microangiopathic haemolytic anaemia, and acute renal failure
LPS sensitizes human serum amyloid P component (HuSAP)+ mice to Shiga toxin 2 (Stx2) As shown in Figure 1A, and consistent with our previous observations [8], HuSAP+ C57BL/6 transgenic mice are completely resistant to 225 pg/g body weight (BW) purified Stx2, in contrast to WT mice which were completely sensitive
HuSAP may still offer some protection since the average survival time (88.9+/210.9 h) of the HuSAP+ mice challenged with Stx2 plus LPS was significantly longer relative to WT mice challenged with Stx2 plus LPS (70.1+/212.4 h)
Summary
Haemolytic-uremic syndrome (HUS) is characterized by a triad of clinical signs including thrombocytopenia, microangiopathic haemolytic anaemia, and acute renal failure. Shiga toxin 2 (Stx2) is more commonly associated with HUS than Stx1 [1,2], immunoglobulin-depleted human serum possesses an innate ability to neutralize the cytotoxic activity of Stx2 [3]. The factor responsible for this neutralizing activity was identified by Kimura et al as human serum amyloid P component (HuSAP) [4]. We previously demonstrated that HuSAP inhibits Stx from binding its cellular receptor, the glycolipid globotriaosylceramide (Gb3) [7]. This activity is apparently unique to HuSAP, since serum from a variety of other species, including mice, fails to neutralize Stx2 [4]. We showed that the initial toxinmediated renal damage in humans can occur despite the presence of normal concentrations of HuSAP in their sera
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