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Vol. 16, Issue 2, 824-834, February 2005

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Cdc42 and RhoB Activation Are Required for Mannose Receptor-mediated Phagocytosis by Human Alveolar Macrophages

Jianmin Zhang ^*, Jinping Zhu ^*, Xia Bu , Melanie Cushion , T. Bernard Kinane , Hava Avraham , and Henry Koziel ^* ||

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

Submitted June 8, 2004; Revised November 3, 2004; Accepted November 17, 2004
Monitoring Editor: Suzanne Pfeffer

Human alveolar macrophages (AMs) phagocytose Pneumocystis (Pc) organisms predominantly through mannose receptors, although the molecular mechanism mediating this opsonin-independent process is not known. In this study, using AMs 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 AMs (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 AMs, 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.

Abbreviations used: GTPases, guanosine triphosphatases; HIV, human immunodeficiency virus; PAK-1, p21-activated kinases; ROCK, Rho-associated coiled-coil kinase.

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

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