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MBC in Press, published online ahead of print December 1, 2004
Mol. Biol. Cell 10.1091/mbc.E04-06-0463

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Submitted on June 8, 2004
Revised on November 3, 2004
Accepted on November 17, 2004

Cdc42 and RhoB Activation are Required for Mannose Receptor-Mediated Phagocytosis by Human Alveolar Macrophages

Jianmin Zhang,* Jinping Zhu,* Xia Bu,{dagger} Melanie Cushion,{ddagger} T. Bernard Kinane,{sect} Hava Avraham,{dagger} and Henry Koziel*||

*Division of Pulmonary & Critical Care Medicine and {dagger}Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; {ddagger}VA Medical Center, University of Cincinnati, Cincinnati, OH 45220; {sect}Laboratory of Developmental Immunology, Department of Pediatric Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

Monitoring Editor: Suzanne Pfeffer

Human alveolar macrophages (AM) phagocytose Pneumocystis (Pc) organisms predominantly through mannose receptors, although the molecular mechanism mediating this opsonin-independent process is not known. In this study, using AM from healthy individuals, Pc phagocytosis was associated with focal F-actin polymerization and Cdc42, Rac1 and Rho activation in a time-dependent manner. Phagocytosis was primarily dependent on Cdc42 and RhoB activation (as determined by AM transfection with Cdc42 and RhoB dominant-negative alleles) and mediated predominantly through mannose receptors (as determined by siRNA gene silencing of AM mannose receptors). Pc also promoted PAK-1 phosphorylation, which was also dependent on RhoGTPase activation. HIV infection of AM (as a model for reduced mannose receptor expression and function) was associated with impaired F-actin polymerization, reduced Cdc42 and Rho activation, and markedly reduced PAK-1 phosphorylation in response to Pc organisms. In healthy AM, Pc phagocytosis was partially dependent on PAK activation, but dependent on the Rho effector molecule ROCK. These data provide a molecular mechanism for AM mannose receptor-mediated phagocytosis of unopsonized Pc organisms, that appears distinct from opsonin-dependent phagocytic receptors. Reduced AM mannose receptor-mediated Cdc42 and Rho activation in the context of HIV infection may represent a mechanism that contributes to the pathogenesis of opportunistic pneumonia.

||Corresponding author. E-mail: hkoziel{at}bidmc.harvard.edu




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