ReviewComplement escape of human pathogenic bacteria by acquisition of complement regulators
Introduction
The relationship between micro-organisms and the human immune system is based on numerous complex interactions. Some potentially infectious pathogens live as commensals in symbiosis with the human host and cause disease only under certain circumstances, e.g. when the host's defence system is considerably impaired. On the other hand, discrimination between “self” from “non-self” plays an important role for the elimination of a wide range of invading pathogens and subsequently prevents intruder dissemination through the bloodstream to body regions some distances away from the initial entrance site. Complement exhibits a first-line of defence representing a particularly important and effective part of the human innate immune system which is immediately and directly activated upon entry of a pathogen (Walport, 2001). In general, direct activation of complement via the alternative or the MBLectin pathway (activated by the surface composition of the pathogen) and also by the classical pathway (activated by specific antibodies or surface moieties) results in the formation and deposition of the key complement component C3b. C3b deposition on activator cell surfaces leads to opsonization followed by opsonophagocytosis or formation of the lytic membrane attack complex (MAC) causing complement-mediated killing. Since C3b is generated by all three pathways, it would be beneficial for invading micro-organisms to inhibit complement activation at the key site of the cascade.
There are multiple strategies that micro-organisms can execute to evade recognition or eradication and virtually all pathogens that can systemically infect the host apply at least one, but usually several of these (Würzner, 1999, Würzner, 2003, Sacks and Sher, 2002; Favoreel et al., 2003, Hilleman, 2004, Speth et al., 2004). One strategy of micro-organisms has recently attracted particular interest, namely the ability to acquire fluid-phase complement regulators (Würzner, 1999, Rautemaa and Meri, 1999, Lindahl et al., 2000). Only few reports have been published on the recruitment of – normally membrane-bound – CD59 from the fluid phase for protection against terminal complement attack and lysis: for Escherichia coli (Rautemaa et al., 1998) and Helicobacter pylori (Rautemaa et al., 2001). Most reports, however, have dealt with the adsorption of host derived truly fluid-phase complement regulators, such as factor H, FHL-1, or the C4b binding protein (C4BP), thereby inhibiting and controlling complement activation directly on the surface of the pathogen. Fluid-phase complement regulators are employed for complement subversion by all four major groups of pathogens, not only by bacteria, but also by viruses (Stoiber et al., 1996), fungi (Meri et al., 2002, Meri et al., 2004), and parasites (Diaz et al., 1997). However, only the former, but not the latter three, will be dealt with in detail in this review.
Under normal circumstances, the complement system is tightly controlled by a number of specific glycoproteins present in the fluid phase (e.g. factor H, FHL-1, C4b binding protein, and C1 inhibitor) and also on cell membranes (e.g. CR1/CD35, CR2/CD21, MCP/CD46, DAF/CD55, and protectin/CD59) to prevent inappropriate complement activation and cell destruction (Morgan and Harris, 1999). Factor H, a 150 kDa plasma protein, is the central fluid-phase regulator of the alternative complement pathway. This plasma protein is structurally composed of 20 individually folded short consensus repeats (SCRs) or complement control protein modules (CCPs) (Nilsson and Müller-Eberhard, 1965, Ripoche et al., 1988) (Fig. 1A). FHL-1, a 42 kDa plasma protein, is identical with the first seven SCRs of factor H and includes an extension of four hydrophobic amino acid residues (Ser–Phe–Thr–Leu) at its C-terminus (Fig. 1A). While factor H is found in plasma at a concentration of approximately 500 μg/ml, FHL-1 is present in plasma at significantly lower concentration of 10–50 μg/ml. Both plasma proteins control the alternative pathway of complement activation at the level of C3b by competing with factor B for binding to C3b. These regulators accelerate the decay of the C3 convertase, C3bBb (decay-accelerating activity), and act as cofactors for factor I-mediated degradation of C3b (Kühn et al., 1995, Pangburn et al., 1977, Whaley and Ruddy, 1976, Zipfel and Skerka, 1999, Zipfel et al., 2002) (Fig. 1B).
C4BP, a 570 kDa molecule, is the key fluid-phase complement regulator of the classical pathway and has the most complex structure comprising of seven identical α-chains linked by disulphide bridges, and a single short β-chain arranged in a spider-like fashion (Scharfstein et al., 1978, Nagasawa et al., 1983, Blom, 2002). The N-terminus of each α-chain is organized into eight SCRs whereby the β-chain attached to the central core region of the molecule is composed of three SCRs (Fig. 1A). C4BP is found in plasma at a concentration of 200–250 μg/ml. C4BP acts as cofactor for factor I-mediated inactivation/degradation of C4b to C4d, and facilitates dissociation of C2a from the classical pathway C3 convertase C4b2a, thereby preventing formation of new convertase and down-regulating activation of the classical pathway (Fujita et al., 1978, Fujita and Nussenzweig, 1979) (Fig. 1C).
Section snippets
Cocci
Gram-positive bacteria such as group A streptococci (Streptococcus pyogenes), group B streptococci (Streptococcus agalactiae), and pneumococci (Streptococcus pneumoniae) represent human pathogenic micro-organisms that cause widespread morbidity and mortality, especially in industrial countries.
S. pyogenes, the most common and virulent pathogen, is responsible for a wide range of suppurative infections ranging from mild infections (e.g. pharyngitis and impetigo) to severe and invasive infections
Acknowledgments
The work of the authors is funded by the Austrian Fonds zur Förderung der wissenschaftlichen Forschung (P-17043-B13) and the European Union (EU-QLRT-CT-2001-01039) to R.W.
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