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Infection and Immunity, March 2009, p. 1008-1014, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.00976-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Defects in Innate Immunity Predispose C57BL/6J-Leprdb/Leprdb Mice to Infection by Staphylococcus aureus{triangledown}

Sunny Park, Jeremy Rich, Frank Hanses, and Jean C. Lee*

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Received 4 August 2008/ Returned for modification 5 September 2008/ Accepted 16 December 2008

Foot and ankle infections are the most common cause of hospitalization among diabetic patients, and Staphylococcus aureus is a major pathogen implicated in these infections. Patients with insulin-resistant (type 2) diabetes are more susceptible to bacterial infections than nondiabetic subjects, but the pathogenesis of these infections is poorly understood. C57BL/6J-Leprdb/Leprdb (hereafter, db/db) mice develop type 2 diabetes due to a recessive, autosomal mutation in the leptin receptor. We established a S. aureus hind paw infection in diabetic db/db and nondiabetic Lepr+/+ (+/+) mice to investigate host factors that predispose diabetic mice to infection. Nondiabetic +/+ mice resolved the S. aureus hind paw infection within 10 days, whereas db/db mice with persistent hyperglycemia developed a chronic infection associated with a high bacterial burden. Diabetic db/db mice showed a more robust neutrophil infiltration to the infection site and higher levels of chemokines in the infected tissue than +/+ mice. Blood from +/+ mice killed S. aureus in vitro, whereas db/db blood was defective in bacterial killing. Compared with peripheral blood neutrophils from +/+ mice, db/db neutrophils demonstrated a diminished respiratory burst when stimulated with S. aureus. However, bone marrow-derived neutrophils from +/+ and db/db mice showed comparable phagocytosis and bactericidal activity. Our results indicate that diabetic db/db mice are more susceptible to staphylococcal infection than their nondiabetic littermates and that persistent hyperglycemia modulates innate immunity in the diabetic host.

* Corresponding author. Mailing address: Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. Phone: (617) 525-2652. Fax: (617) 731-1541. E-mail: jclee{at}rics.bwh.harvard.edu

{triangledown} Published ahead of print on 22 December 2008.

Editor: R. P. Morrison

Infection and Immunity, March 2009, p. 1008-1014, Vol. 77, No. 3
0019-9567/09/$08.00+0     doi:10.1128/IAI.00976-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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