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Infection and Immunity, June 2004, p. 3147-3160, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3147-3160.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Pneumocystis Activates Human Alveolar Macrophage NF-{kappa}B Signaling through Mannose Receptors

Jianmin Zhang,1 Jinping Zhu,1 Amy Imrich,2 Melanie Cushion,3 T. Bernard Kinane,4 and Henry Koziel1*

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School,1 Respiratory Biology, Harvard School of Public Health,2 Laboratory of Developmental Immunology, Department of Pediatric Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,4 Veterans Administration Medical Center, University of Cincinnati, Cincinnati, Ohio3

Received 12 November 2003/ Returned for modification 22 December 2003/ Accepted 6 February 2004

Alveolar macrophages (AM) represent important effector cells in the innate immune response to the AIDS-related pathogen Pneumocystis, but the early AM host defense signaling events are poorly defined. Using AM from healthy individuals, we showed in the present study that Pneumocystis organisms stimulate AM NF-{kappa}B p50 and p65 nuclear translocation in a time-dependent and multiplicity-of-infection-dependent manner as determined by electrophoretic mobility shift assay and immunofluorescence microscopy and that NF-{kappa}B nuclear translocation is associated with I-{kappa}B phosphorylation. Importantly, competitive inhibition of mannose receptor and targeted short interfering RNA-mediated gene suppression of mannose receptor mRNA and protein is associated with complete elimination of NF-{kappa}B nuclear translocation in response to Pneumocystis. Furthermore, human immunodeficiency virus (HIV) infection of AM (as a model human disease state of reduced AM mannose receptor expression and function) inhibits Pneumocystis-mediated NF-{kappa}B nuclear translocation and is associated with reduced I-{kappa}B phosphorylation and reduced interleukin-8 (IL-8) release. In contrast, NF-{kappa}B nuclear translocation and IL-8 release in response to lipopolysaccharide are intact in AM from both healthy and HIV-infected individuals, indicating that the observed impairment is not a global disturbance of the NF-{kappa}B pathway. Thus, in addition to phagocytic and endocytic effector functions, the present study identifies mannose receptors as pattern recognition receptors capable of NF-{kappa}B activation in response to infectious non-self challenge. AM mannose receptor-mediated NF-{kappa}B activation may represent an important mechanism of the host cell response to Pneumocystis, and altered NF-{kappa}B activation in the context of HIV infection may impair a critical innate immune signaling response and may contribute to pathogenesis of opportunistic lung infections.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, Kirstein Hall, Room E/KSB-23, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-4487. Fax: (617) 667-4849. E-mail: hkoziel{at}bidmc.harvard.edu.

Editor: T. R. Kozel

Infection and Immunity, June 2004, p. 3147-3160, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3147-3160.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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