Human Serum Amyloid P Component Protects againstEscherichia coliO157:H7 Shiga Toxin 2 In Vivo: Therapeutic Implications for Hemolytic‐Uremic Syndrome

Abstract

Shiga toxin (Stx) 2 causes hemolytic-uremic syndrome (HUS), an intractable and often fatal complication of enterohemorrhagic Escherichia coli O157:H7 infection. Here, we show that serum amyloid P component (SAP), a normal human plasma protein, specifically protects mice against the lethal toxicity of Stx2, both when injected into wild-type mice and when expressed transgenically; in the presence of human SAP, there was greatly reduced in vivo localization of Stx2 to the kidneys, suggesting a possible mechanism of protection. In humans, circulating SAP concentrations did not differ between patients with suspected enterohemorrhagic E. coli infection with antibodies to E. coli O157:H7 lipopolysaccharide and those without antibodies or between patients with HUS and those without it. However, the potent protection conferred by human SAP in the mouse model suggests that infusion of supplemental SAP may be a useful novel therapeutic approach to the treatment of this devastating condition.

Protection of Human Podocytes from Shiga Toxin 2-Induced Phosphorylation of Mitogen-Activated Protein Kinases and Apoptosis by Human Serum Amyloid P Component

“…Nevertheless, there is experimental evidence that SAP can contribute to host defense against certain bacterial infections (17). SAP neutralizes Stx2, but not Stx1, in vitro, and human SAP protects mice from Stx2-induced disease (14). The Stx2-neutralizing effect is not present in the sera of nonhuman species tested so far (15), consistent with the much higher binding avidity of human SAP than mouse SAP to other known ligands (18).…”

“…Armstrong and colleagues identified SAP as a potential neutralizing factor (14). SAP is synthesized in the liver and circulates in the blood at levels of 8 to 55 mg/liter (42).…”

“…It has been suggested that neurological involvement may be due to deficiency or impaired function of an Stx2-neutralizing factor (13) in affected patients, in which case plasma supply and exchange might be beneficial. Various candidates for such a neutralizing factor have been investigated, and serum amyloid P component (SAP) appears to be the most promising (14,15). SAP is one member of the pentraxin family; the other member is C-reactive protein (CRP) (16).…”

Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome

“…However, whether this accounts for the majority of clinical symptoms found in EHEC-associated HUS or not is still unknown, with the consequence that an effective therapy is as yet unavailable (5). Armstrong et al (6) have found that human serum amyloid P is binding to Stx2 and protecting mice against the lethal challenge by i.v. administered Stx2.…”

The bundlin pilin protein of enteropathogenic Escherichia coli is an N-acetyllactosamine-specific lectin

“…Strain % HEp-2 cells with adherent EPEC as described in a previous article (Armstrong et al, 2006), and the 125 I-bundlin was immediately separated from the reaction by-products using a 0.7 ¥ 15 cm Sephadex (GE HealthCare) G25 gel-filtration column. The protein concentration and specific activity (8.68 ¥ 10 5 cpm mg -1 ) of the 125 I-bundlin preparation were determined as described elsewhere (Armstrong and Peppler, 1987).…”