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IFN- Regulated Chemokine Production Determines the Outcome of Staphylococcus aureus Infection¹

Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Immunomodulatory therapy represents an attractive approach in treating multidrug-resistant infections. Developing this therapy necessitates a lucid understanding of host defense mechanisms. Neutrophils represent the first line of systemic defense during Staphylococcus aureus infections. However, recent research suggests that survival of S. aureus inside neutrophils may actually contribute to pathogenesis, indicating that neutrophil trafficking to the infection site must be tightly regulated to ensure efficient microbial clearance. We demonstrate that neutrophil-regulating T cells are activated during S. aureus infection and produce cytokines that control the local neutrophil response. S. aureus capsular polysaccharide activates T cell production of IFN- in a novel MHC class II-dependent mechanism. During S. aureus surgical wound infection, the presence of IFN- at the infection site depends upon βTCR⁺ cells and functions to regulate CXC chemokine production and neutrophil recruitment in vivo. We note that the reduced neutrophil response seen in IFN-^–/– mice during S. aureus infection is associated with reduced tissue bacterial burden. CXC chemokine administration to the infection site resulted in an increased survival of viable S. aureus inside neutrophils isolated from the wound. These data demonstrate that T cell-derived IFN- generates a neutrophil-rich environment that can potentiate S. aureus pathogenesis by facilitating bacterial survival within the neutrophil. These findings suggest avenues for novel immunomodulatory approaches to control S. aureus infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01AI52397 (to A.O.T.).

² Address correspondence and reprint requests to Dr. Rachel M. McLoughlin, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail address: rmcloughlin{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; WT, wild type; GalU, polygalacturonic acid; CP, capsular polysaccharide; MPO, myeloperoxidase; MHCII, MHC class; SEA, staphylococcal enterotoxin A; TT, tetanus toxoid; PNAG, poly-N-acetylglucosamine.

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