The Molecular Mechanism of Shiga Toxin Stx2e Neutralization by a Single-domain Antibody Targeting the Cell Receptor-binding Domain

Shiga toxin Stx2e is the major known agent that causes edema
disease in newly weaned pigs. This severe disease is characterized
by neurological disorders, hemorrhagic lesions, and frequent
fatal outcomes. Stx2e consists of an enzymatically active
A subunit and five B subunits that bind to a specific glycolipid
receptor on host cells. It is evident that antibodies binding to the
A subunit or the B subunits of Shiga toxin variants may have the
capability to inhibit their cytotoxicity. Here, we report the discovery
and characterization of a VHH single domain antibody
(nanobody) isolated from a llama phage display library that confers
potent neutralizing capacity against Stx2e toxin.Wefurther
present the crystal structure of the complex formed between the
nanobody (NbStx2e1) and the Stx2e toxoid, determined at 2.8Å
resolution. Structural analysis revealed that for each B subunit
of Stx2e, one NbStx2e1 is interacting in a head-to-head orientation
and directly competing with the glycolipid receptor binding
site on the surface of the B subunit. The neutralizing NbStx2e1
can in the future be used to prevent or treat edema disease.

Jaar van publicatie:2014

Trefwoorden:Shiga toxin, edema disease, VHH single domain antibody