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Infection and Immunity, September 2005, p. 5892-5902, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5892-5902.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Francisella tularensis Enters Macrophages via a Novel Process Involving Pseudopod Loops

Daniel L. Clemens,* Bai-Yu Lee, and Marcus A. Horwitz

Division of Infectious Diseases, Department of Medicine, University of California-Los Angeles School of Medicine, Center for Health Sciences, Los Angeles, California 90095-1688

Received 24 November 2004/ Returned for modification 22 December 2004/ Accepted 27 April 2005

Intracellular bacterial pathogens employ a variety of strategies to invade their eukaryotic host cells. From an ultrastructural standpoint, the processes that bacteria employ to invade their host cells include conventional phagocytosis, coiling phagocytosis, and ruffling/triggered macropinocytosis. In this paper, we describe a novel process by which Francisella tularensis, the agent of tularemia, enters host macrophages. F. tularensis is a remarkably infectious facultative intracellular bacterial parasite—as few as 10 bacteria can cause life-threatening disease in humans. However, the ultrastructure of its uptake and the receptor mechanisms that mediate its uptake have not been reported previously. We have used fluorescence microscopy and electron microscopy to examine the adherence and uptake of a virulent recent clinical isolate of F. tularensis, subspecies tularensis, and the live vaccine strain (LVS), subspecies holarctica, by human macrophages. We show here that both strains of F. tularensis enter human macrophages by a novel process of engulfment within asymmetric, spacious pseudopod loops, a process that differs ultrastructurally from all previously described uptake mechanisms. We demonstrate also that adherence and uptake of F. tularensis by macrophages is strongly dependent upon complement receptors and upon serum with intact complement factor C3 and that uptake requires actin microfilaments. These findings have significant implications for understanding the intracellular biology and virulence of this extremely infectious pathogen.

* Corresponding author. Mailing address: Division of Infectious Diseases, Dept. of Medicine, UCLA School of Medicine, CHS 37-121, 10833 LeConte Ave., Los Angeles, CA 90095-1688. Phone: (310) 825-9324. Fax: (310) 794-7156. E-mail: dclemens{at}mednet.ucla.edu.

Editor: D. L. Burns

Infection and Immunity, September 2005, p. 5892-5902, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5892-5902.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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