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Infection and Immunity, October 2009, p. 4487-4495, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00530-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Phagocytosis Inhibits F-Actin-Enriched Membrane Protrusions Stimulated by Fractalkine (CX3CL1) and Colony-Stimulating Factor 1 {triangledown}

Yong Luo,1 Beth M. Isaac,2 Arturo Casadevall,1,3,{dagger} and Dianne Cox2,4*,{dagger}

Department of Microbiology and Immunology,1 Department of Anatomy and Structural Biology,2 Department of Medicine,3 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 104614

Received 13 May 2009/ Returned for modification 15 June 2009/ Accepted 8 July 2009

Cryptococcus neoformans is the only encapsulated human-pathogenic fungus and a facultative intracellular pathogen that can reside in macrophages without host cell lysis. In the present study, we investigated how phagocytosis of C. neoformans affected the macrophage response to chemoattractants such as fractalkine (FKN) (CX3CL1) and colony-stimulating factor 1 (CSF-1). Phagocytosis of immunoglobulin G (IgG)-opsonized C. neoformans and IgG- or C3bi-opsonized sheep erythrocytes was performed using a RAW 264.7 subline (LR5 cells) and bone marrow-derived macrophages (BMM). The chemotactic response to FKN or CSF-1 was quantitated by measurement of the formation of F-actin-enriched membrane protrusions (ruffles), which showed that FKN or CSF-1 stimulated strong transient ruffling in both LR5 cells and BMM. This stimulated cell ruffling was inhibited by phagocytosis in an intracellular-pathogen-number-dependent manner. The inhibition of ruffling was not simply a result of reduced membrane availability since membrane sequestration by sucrose treatment did not inhibit the ruffling response. The phagocytosis process was required to inhibit ruffling as BMM from Fc{gamma}R–/– mice that bound C. neoformans but did not ingest it retained the ability to ruffle in response to chemoattractants. These results imply that the inhibition of FKN- or CSF-1-stimulated cell ruffling was a direct consequence of the phagocytosis process. Since cell ruffling is a prelude to chemotaxis, this observation links two functions of macrophages that are critical to host defense, chemotaxis and phagocytosis. Phagocytosis-induced chemotactic suppression may enhance host defense by keeping these antimicrobial effector cells at infected sites and reduce the likelihood of microbial spread by wandering macrophages containing infectious cargo.

* Corresponding author. Mailing address: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461. Phone: (718) 430-4005. Fax: (718) 430-8996. E-mail: dcox{at}aecom.yu.edu

{triangledown} Published ahead of print on 20 July 2009.

Editor: J. B. Bliska

{dagger} A.C. and D.C. are both senior authors.

Infection and Immunity, October 2009, p. 4487-4495, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00530-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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