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Infection and Immunity, May 2008, p. 1931-1939, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01282-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Intracellular Neutralization of Shiga Toxin 2 by an A Subunit-Specific Human Monoclonal Antibody{triangledown} ,{dagger}

Greice Krautz-Peterson,1 Susan Chapman-Bonofiglio,1 Karen Boisvert,2 Hanping Feng,1 Ira M. Herman,3 Saul Tzipori,1 and Abhineet S. Sheoran1*

Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts 01536,1 Comparative Pathology, NEPRC, Harvard University, Southborough, Massachusetts 01772,2 Department of Physiology, Tufts Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 021113

Received 19 September 2007/ Returned for modification 1 October 2007/ Accepted 5 February 2008

Infection of children with Shiga toxin (Stx)-producing Escherichia coli (STEC) is the leading cause of hemolytic-uremic syndrome (HUS). Stx2, one of two toxins liberated by the bacteria, is directly linked with HUS. We have previously shown that Stx2-specific human monoclonal antibodies (HuMAbs) protect mice and piglets from fatal systemic complications of Stx2. The present study investigates the mechanisms by which our most efficacious A- and B-subunit-specific HuMAbs neutralize the cytotoxic effects of Stx2 in vitro. Whereas the B-subunit-specific HuMAb 5H8 blocked binding of Stx2 to its receptor on the cell surface, the A-subunit-specific HuMAb 5C12 did not interfere with the toxin-receptor binding. Further investigations revealed that 5C12 did not block endocytosis of Stx2 by HeLa cells as both Stx2 and 5C12 colocalized with early endosomes. However, 5C12 blocked the retrograde transport of the toxin into the Golgi and the endoplasmic reticulum, preventing the toxin from entering the cytosol where the toxin exerts its cytotoxic effect. The endocytosed 5C12/Stx2 complexes appear to be rapidly transported to the plasma membrane and/or to the slow recycling perinuclear compartments, followed by their slow recycling to the plasma membrane, and release into the extracellular environment.

* Corresponding author. Mailing address: Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, 200 Westboro Rd., North Grafton, MA 01536. Phone: (508) 839-7939. Fax: (508) 839-7911. E-mail: abhineet.sheoran{at}tufts.edu

{triangledown} Published ahead of print on 19 February 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: S. R. Blanke

Infection and Immunity, May 2008, p. 1931-1939, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01282-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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