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Infection and Immunity, April 2009, p. 1376-1382, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00940-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Critical Role of NOD2 in Regulating the Immune Response to Staphylococcus aureus

Hitesh S. Deshmukh,¹ James B. Hamburger,² Sun Hee Ahn,¹ Dewey G. McCafferty,² Suxiao R. Yang,¹ and Vance G. Fowler Jr.^1,3*

Department of Medicine, Duke University Medical Center, Durham, North Carolina,¹ Department of Chemistry, Duke University, Durham, North Carolina,² Duke Clinical Research Institute, Durham, North Carolina³

Received 28 July 2008/ Returned for modification 2 October 2008/ Accepted 4 January 2009

NOD2 (the nucleotide-binding oligomerization domain containing protein 2) is known to be involved in host recognition of bacteria, although its role in the host response to Staphylococcus aureus infection is unknown. NOD2-deficient (Nod2^–/–) mice and wild-type (WT) littermate controls were injected intraperitoneally with S. aureus suspension (10⁷ bacteria/g of body weight), and their survival was monitored. Cultured bone marrow-derived neutrophils were harvested from Nod2^–/– and WT mice and tested for cytokine production and phagocytosis. Compared to WT mice, Nod2^–/– mice were significantly more susceptible to S. aureus infection (median survival of 1.5 days versus >5 days; P = 0.003) and had a significantly higher bacterial tissue burden. Cultured bone marrow-derived neutrophils from Nod2^–/– and WT mice had similar levels of peritoneal neutrophil recruitment and intracellular killing, but bone marrow-derived neutrophils from Nod2^–/– mice had significantly reduced ability to internalize fluorescein-labeled S. aureus. Nod2^–/– mice had significantly higher levels of Th1-derived cytokines in serum (tumor necrosis factor alpha, gamma interferon, and interleukin-2 [IL-2]) compared to WT mice, whereas the levels of Th2-derived cytokines (IL-1β, IL-4, IL-6, and IL-10) were similar in Nod2^–/– and WT mice. Thus, mice deficient in NOD2 are more susceptible to S. aureus. Increased susceptibility is due in part to defective neutrophil phagocytosis, elevated serum levels of Th1 cytokines, and a higher bacterial tissue burden.

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* Corresponding author. Mailing address: Duke University Medical Center, MHS, P.O. Box 3281, Durham, NC 27710-3281. Phone: (919) 684-4335. Fax: (919) 684-8902. E-mail: fowle003{at}mc.duke.edu

Published ahead of print on 12 January 2009.

Editor: J. L. Flynn

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Infection and Immunity, April 2009, p. 1376-1382, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.00940-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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