This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clemens, D. L. Articles by Horwitz, M. A. Search for Related Content PubMed PubMed Citation Articles by Clemens, D. L. Articles by Horwitz, M. A.

Francisella tularensis Enters Macrophages via a Novel Process Involving Pseudopod Loops

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.

Editor: D. L. Burns

This article has been cited by other articles:

• Chakraborty, S., Monfett, M., Maier, T. M., Benach, J. L., Frank, D. W., Thanassi, D. G. (2008). Type IV Pili in Francisella tularensis: Roles of pilF and pilT in Fiber Assembly, Host Cell Adherence, and Virulence. Infect. Immun. 76: 2852-2861 [Abstract] [Full Text]  
• Ben Nasr, A., Klimpel, G. R. (2008). Subversion of complement activation at the bacterial surface promotes serum resistance and opsonophagocytosis of Francisella tularensis. J. Leukoc. Biol. 84: 77-85 [Abstract] [Full Text]  
• Tamilselvam, B., Daefler, S. (2008). Francisella Targets Cholesterol-Rich Host Cell Membrane Domains for Entry into Macrophages. J. Immunol. 180: 8262-8271 [Abstract] [Full Text]  
• McLendon, M. K., Schilling, B., Hunt, J. R., Apicella, M. A., Gibson, B. W. (2007). Identification of LpxL, a Late Acyltransferase of Francisella tularensis. Infect. Immun. 75: 5518-5531 [Abstract] [Full Text]  
• Lindemann, S. R., McLendon, M. K., Apicella, M. A., Jones, B. D. (2007). An In Vitro Model System Used To Study Adherence and Invasion of Francisella tularensis Live Vaccine Strain in Nonphagocytic Cells. Infect. Immun. 75: 3178-3182 [Abstract] [Full Text]  
• CLEMENS, D. L., HORWITZ, M. A. (2007). Uptake and Intracellular Fate of Francisella tularensis in Human Macrophages. Ann. N. Y. Acad. Sci. 1105: 160-186 [Abstract] [Full Text]  
• ELKINS, K. L., COWLEY, S. C., BOSIO, C. M. (2007). Innate and Adaptive Immunity to Francisella. Ann. N. Y. Acad. Sci. 1105: 284-324 [Abstract] [Full Text]  
• Hotta, A., Uda, A., Fujita, O., Tanabayashi, K., Yamada, A. (2007). Preparation of Monoclonal Antibodies for Detection and Identification of Francisella tularensis. CVI 14: 81-84 [Abstract] [Full Text]  
• McCaffrey, R. L., Allen, L.-A. H. (2006). Francisella tularensis LVS evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape. J. Leukoc. Biol. 80: 1224-1230 [Abstract] [Full Text]  
• Ben Nasr, A., Haithcoat, J., Masterson, J. E., Gunn, J. S., Eaves-Pyles, T., Klimpel, G. R. (2006). Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC): uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria. J. Leukoc. Biol. 80: 774-786 [Abstract] [Full Text]  
• Balagopal, A., MacFarlane, A. S., Mohapatra, N., Soni, S., Gunn, J. S., Schlesinger, L. S. (2006). Characterization of the Receptor-Ligand Pathways Important for Entry and Survival of Francisella tularensis in Human Macrophages. Infect. Immun. 74: 5114-5125 [Abstract] [Full Text]  
• Schulert, G. S., Allen, L.-A. H. (2006). Differential infection of mononuclear phagocytes by Francisella tularensis: role of the macrophage mannose receptor. J. Leukoc. Biol. 80: 563-571 [Abstract] [Full Text]