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Early NK Cell-Derived IFN- Is Essential to Host Defense in Neutropenic Invasive Aspergillosis¹

Stacy J. Park^*, Molly A. Hughes, Marie Burdick, Robert M. Strieter and Borna Mehrad^2,*,

^* Department of Microbiology, and Divisions of Pulmonary and Critical Care Medicine and Infectious Diseases, Department of Medicine, University of Virginia, Charlottesville, VA 22908

Invasive aspergillosis is among the most common human fungal infections and occurs in patients with severe and complex defects in immune responses. NK cells have previously been found to be important in host defense against this infection, but the mechanism of this effect is not known. We hypothesized that NK cells mediate their protective effect in invasive aspergillosis by acting as the major source of IFN- during early infection. We found that, in the lungs of neutropenic mice with invasive aspergillosis, NK cells were the major population of cells capable of generating IFN- during early infection. Depletion of NK cells resulted in reduced lung IFN- levels and increased lung fungal load that was independent of T and B cell subsets. Depletion of NK cells and absence of IFN- resulted in a similar increase in susceptibility to the infection, but depletion of NK cells in IFN--deficient hosts did not result in further increase in severity of the infection. NK cell-derived IFN- caused enhanced macrophage antimicrobial effects in vitro and also resulted in greater expression of IFN-inducible chemokines in the lungs. Finally, transfer of activated NK cells from wild-type, but not IFN--deficient hosts, resulted in greater pathogen clearance from the lungs of both IFN--deficient and wild-type recipients. Taken together, these data indicate that NK cells are the main source of early IFN- in the lungs in neutropenic invasive aspergillosis, and this is an important mechanism in the defense against this 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 work was supported by National Institutes of Health Grant HL73848 and an American Lung Association Career Investigator Award (to B.M.).

² Address correspondence and reprint requests to Dr. Borna Mehrad, P.O. Box 800546, Charlottesville, VA 22908. E-mail address: Mehrad{at}Virginia.edu

³ Abbreviation used in this paper: WT, wild type.

This article has been cited by other articles:

				S. J. Park and B. Mehrad Innate Immunity to Aspergillus Species Clin. Microbiol. Rev., October 1, 2009; 22(4): 535 - 551. [Abstract] [Full Text] [PDF]