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Infection and Immunity, September 2008, p. 3951-3958, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00109-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CD46 Contributes to the Severity of Group A Streptococcal Infection {triangledown}

Lena Lövkvist,1,{dagger} Hong Sjölinder,1,{dagger} Rahma Wehelie,1 Helena Aro,1 Anna Norrby-Teglund,3 Laura Plant,2 and Ann-Beth Jonsson1*

Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, 751 23 Uppsala, Sweden,1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden,2 Center of Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Solna, Sweden3

Received 25 January 2008/ Returned for modification 9 April 2008/ Accepted 6 June 2008

Streptococcus pyogenes (group A Streptococcus) is a human pathogen that causes a wide variety of diseases ranging from uncomplicated superficial infections to severe infections such as streptococcal toxic shock syndrome and necrotizing fasciitis. These bacteria interact with several host cell receptors, one of which is the cell surface complement regulator CD46. In this study, we demonstrate that infection of epithelial cells with S. pyogenes leads to the shedding of CD46 at the same time as the bacteria induce apoptosis and cell death. Soluble CD46 attached to the streptococcal surface, suggesting that bacteria might bind available extracellular CD46 as a strategy to survive and avoid host defenses. The protective role of human CD46 was demonstrated in ex vivo whole-blood assays showing that the growth of S. pyogenes was enhanced in blood from mice expressing human CD46. Finally, in vivo experimental infection showed that bacteremia levels, arthritis frequency, and mortality were higher in CD46 transgenic mice than in nontransgenic mice. Taken together, these results argue that bacterial exploitation of human CD46 enhances bacterial survival and represents a novel pathogenic mechanism that contributes to the severity of group A streptococcal disease.

* Corresponding author. Mailing address: Department of Medical Biochemistry and Microbiology, Uppsala University, SE 75123 Uppsala, Sweden. Phone: 46-(0)18-4714507. Fax: 46-(0)18-4714673. E-mail: Ann-Beth.Jonsson{at}imbim.uu.se

{triangledown} Published ahead of print on 23 June 2008.

Editor: J. N. Weiser

{dagger} L.L. and H.S. contributed equally.

Infection and Immunity, September 2008, p. 3951-3958, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00109-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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