Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis
Brad E. Morrison, … , Jill M. Mooney, Borna Mehrad
Brad E. Morrison, … , Jill M. Mooney, Borna Mehrad
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1862-1870. https://doi.org/10.1172/JCI18125.
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Article Infectious disease

Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis

Abstract

Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2–mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection.

Authors

Brad E. Morrison, Stacy J. Park, Jill M. Mooney, Borna Mehrad

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Role of MCP-1/CCL2 in in vivo recruitment of NK cells to the lungs in in...
Role of MCP-1/CCL2 in in vivo recruitment of NK cells to the lungs in invasive aspergillosis. Cultured NK cells were left unlabeled or labeled with the vital cytoplasmic fluorochrome, CFSE, and transferred to neutrophil-depleted mice before intratracheal challenge with A. fumigatus conidia or vehicle. Infected mice were treated with PBS or neutralizing anti–MCP-1/CCL2 Ab, and lungs were examined for the presence of CFSE-labeled cells after 1 day. (a) A representative scatter diagram of total lung cells, demonstrating the gate used in b. (b) Representative scatter diagrams from each group, gated on lung CD3– NK1.1+ cells in a. The upper-right quadrants contain transferred CFSE+ NK cell populations used for statistical comparisons in c. (c) Mean ± SEM of the number of lung CFSE+ CD3– NK cells in each group (n = 3–5 per group). *P < 0.05 compared with uninfected mice given labeled cells; **P < 0.05 compared with infected mice with PMN depletion.