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* Department of Pathology and Molecular Medicine and Division of Infectious Diseases, Center for Gene Therapeutics, and
Department of Biology, McMaster University, Hamilton, and
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
Staphylococcus aureus remains a common cause of nosocomial bacterial infections and are often antibiotic resistant. The role of NK cells and IL-15 and their relationship in host defense against extracellular bacterial pathogens including S. aureus remain unclear. We have undertaken several approaches to address this issue using wild type (WT), IL-15 gene knock-out (KO), and NK cell-depleted mouse models. Upon pulmonary staphylococcal infection WT mice had markedly increased activated NK cells, but not NKT or 
T cells, in the airway lumen that correlated with IL-15 production in the airway and with alveolar macrophages. In vitro exposure to staphylococcal products and/or coculture with lung macrophages directly activated NK cells. In contrast, lung macrophages better phagocytosed S. aureus in the presence of NK cells. In sharp contrast to WT controls, IL-15 KO mice deficient in NK cells were found to be highly susceptible to pulmonary staphylococcal infection despite markedly increased neutrophils and macrophages in the lung. In further support of these findings, WT mice depleted of NK cells were similarly susceptible to staphylococcal infection while they remained fully capable of IL-15 production in the lung at levels similar to those of NK-competent WT hosts. Our study thus identifies a critical role for NK cells in host defense against pulmonary extracellular bacterial infection and suggests that IL-15 is involved in this process via its indispensable effect on NK cells, but not other innate cells. These findings hold implication for the development of therapeutics in treating antibiotic-resistant S. aureus infection.
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 study is supported by funds from the Canadian Institutes for Health Research.
2 Address correspondence and reprint requests to Dr. Zhou Xing, Room 4012, Michael G. DeGroote Centre for Learning and Discovery, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada. E-mail address: xingz{at}mcmaster.ca
3 Abbreviations used in this paper: WT, wild type; BAL, bronchoalveolar lavage; cRPMI, complete RPMI medium; i.t., intratracheal; Staph-GFP, S. aureus strain Newman expressing GFP; KO, knockout; PGN, peptidoglycan; PMN, polymorphonuclear; TSA, tryptic soy agar.
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