Complement Opsonins are deposited at the surafce of Francisella Tularensis, an intracellular Bacteria that Subverts Complement Activation

This recent article published in the Journal of leukocyte Biology in July 2008 describes how francisella tularencis (Ft), an intracellular bacteria subverts an important innate immune system module: the complement system. This paper provides a detailed analysis of the early complement activation pathways at the level of C3b/C4b. It is shown that Ft activates both the classical and alternative pathways of complement in non-immune human serum and that deposition of C3 appear to play a significant role in the phagocytosis of bacteria by immature human dendritic cells (DC). The analysis of complement activation pathways showed that the Ft exploits human complement in order to facilitate its own uptake by phagocytic cells, while, at the same time, it binds regulators of complement activation (RCAs) that promote its resistance to complement lysis. The preliminary results show that Ft expresses fH-binding proteins, which are proposed to be responsible for the resistance of Ft to complement-mediated killing. The summury for this article is reproduced here but the full article can be accessed at the Journal's page.

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.