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Infection and Immunity, February 2009, p. 860-866, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00995-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Host Glycosaminoglycan Confers Susceptibility to Bacterial Infection in Drosophila melanogaster{triangledown}

Miriam J. Baron,1* Sandra L. Wong,1 Kent Nybakken,2,{dagger} Vincent J. Carey,1 and Lawrence C. Madoff1,{ddagger}

Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts 02115,1 Department of Genetics, Harvard Medical School, Boston, Massachusetts2

Received 8 August 2008/ Returned for modification 28 September 2008/ Accepted 22 November 2008

Many pathogens engage host cell surface glycosaminoglycans, but redundancy in pathogen adhesins and host glycosaminoglycan-anchoring proteins (heparan sulfate proteoglycans) has limited the understanding of the importance of glycosaminoglycan binding during infection. The alpha C protein of group B streptococcus, a virulence determinant for this neonatal human pathogen, binds to host glycosaminoglycan and mediates the entry of bacteria into human cells. We studied alpha C protein-glycosaminoglycan binding in Drosophila melanogaster, whose glycosaminoglycan repertoire resembles that of humans but whose genome includes only three characterized membrane heparan sulfate proteoglycan genes. The knockdown of glycosaminoglycan polymerases or of heparan sulfate proteoglycans reduced the cellular binding of alpha C protein. The interruption of alpha C protein-glycosaminoglycan binding was associated with longer host survival and a lower bacterial burden. These data indicate that the glycosaminoglycan-alpha C protein interaction involves multiple heparan sulfate proteoglycans and impairs bacterial killing. Host glycosaminoglycans, anchored by multiple proteoglycans, thereby determine susceptibility to infection. Because there is homology between Drosophila and human glycosaminoglycan/proteoglycan structures and many pathogens express glycosaminoglycan-binding structures, our data suggest that interfering with glycosaminoglycan binding may protect against infections in humans.

* Corresponding author. Mailing address: Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-0752. Fax: (617) 731-1541. E-mail: mbaron{at}partners.org

{triangledown} Published ahead of print on 1 December 2008.

Editor: A. Camilli

{dagger} Present address: Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472.

{ddagger} Present address: University of Massachusetts Medical School, 305 South Street, Jamaica Plain, MA 02130.

Infection and Immunity, February 2009, p. 860-866, Vol. 77, No. 2
0019-9567/09/$08.00+0     doi:10.1128/IAI.00995-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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