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Published online before print April 22, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807526

Received for publication August 7, 2007.
Revised February 21, 2008.
Accepted for publication March 3, 2008.

Article

Subversion of complement activation at the bacterial surface promotes serum resistance and opsonophagocytosis of Francisella tularensis

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA

^@ To whom correspondence should be addressed. E-mail: abbennas{at}utmb.edu.

	Abstract

Francisella tularensis (Ft) is resistant to serum but requires complement factor C3-derived opsonins for uptake by phagocytic cells and subsequent intracellular growth. In this study, we show that C3 fragments, deposited on Ft, are detected by anti-C3d and -iC3b mAb and that the classical and the alternative pathways are involved in this event. This was demonstrated using C2-depleted sera and specific inhibitors of the classical-versus-alternative pathways of complement activation. Further, we demonstrate that factor C4b, which is crucial for the classical pathway, is deposited on the surface of Ft. In contrast, the C5b-C9 membrane attack complex (MAC) is not assembled on the surface of Ft, which may explain its resistance to complement killing. Deposition of C3 opsonins leads to enhanced phagocytosis by human immature dendritic cells (DC), which leads to intracellular survival, growth, and DC death. Finally, we show that factor H (fH) can bind to the surface of Ft. We believe our data suggest that important virulence factors for Ft are its ability to bind fH and inactivate C3b to iC3b, which culminates in opsonin-induced uptake for subsequent intracellular growth. C3b inactivation also leads to inefficient MAC assembly, which contributes to the ability of this bacterium to resist complement lysis.

Key Words: complement system • opsonins • bacterial infection

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