Infectious diseases represent a major health, social and economic problem. Although treatment and management of microbial infections has improved during the last decades, the increase in antimicrobial resistance, the emergence of new pathogens and re-emergence of known pathogens form a major threat for health systems in all countries of the world. Therefore new strategies are crucial for fighting infectious diseases. Development of new antimicrobial substances requires a better characterization of pathogen-encoded virulence factors and a more detailed understanding of pathogen-host interaction.
Many pathogens have evolved the means to control host complement response and to this end pathogens utilize multiple evasion strategies to interfere with and to inactivate the powerful complement attack. Analyses of complement evasion strategies used by pathogenic microbes is an active research area and multiple complement evasion strategies have been characterized in recent years.
In several studies, the proteins encoded by the pathogen, which are essential for this immune escape, were identified as novel virulence factors, representing interesting targets for immune interference. Complement and immune evasion strategies at first seem both diverse and unique for each pathogen. However, detailed functional characterization of the escape strategies identifies common features and mechanisms of complement escape.
The ability to escape the elaborate machinery of the human immune system is a key determinant in the virulence of pathogens. Our knowledge of how these escape mechanisms function on a molecular level has increased remarkably in recent years. Identification of the individual pathogenic proteins and their human targets has been one crucial step in this task and the list of complement-targeting proteins is constantly growing. Despite this plethora of complement-binding proteins , their mechanisms of action can be condensed to a few successful strategies: the recruitment or mimicking of complement regulators; the modulation or inhibition of complement proteins by direct interactions; and inactivation by enzymatic degradation. In addition to these strategies, many microorganisms also possess passive evasive features-a prominent example is the cell wall of Gram-positive bacteria, which prevents lysis by the membrane attack complex/MAC.
|Complement evasion protein||Variety||Host target|
|Staphylococcal protein A (SpA)||Antibody depletion||IgG|
|Extracellular fibrinogen-binding protein (Efb)||Complement inhibition||C3 and C3b-containing convertases|
|Staphylococcalsuperantigen-like protein-7 (SSL-7)||Complement inhibition||C5|
|Staphylococcus complement inhibitor (SCIN)||Complement inhibition||C3 convertases|
|Complement C2 receptor trispanning protein (CRIT)||Complement inhibition||C2|
|Chemotaxis inhibitory protein of Staphylococcusaureus
|Complement inhibition||C5a receptor (C5aR)|
|Regulators of complement activation (RCA) recruitment||Factor H, factor H-like protein-1 (FHL-1) and C4-binding protein (C4BP)|
|M protein family||Regulators of complement activation (RCA) recruitment||Factor H, FHL-1 and C4BP|
|Variola virus complement-control protein (VCP)||RCA mimicry||C3b and C3 convertases|
|Smallpox protein of complement enzymes (SPICE)||RCA mimicry||C3b and C3 convertases|
|Staphylokinase||Proteolytic degradation||C3b and IgG (by activation of plasmin)|
|Pseudomonas elastase (PaE)||Proteolytic degradation||C3|
|56 kDa protease||Proteolytic degradation||C5a|
1. Lambris J D, et al. (2008). Complement evasion by human pathogens. Nature Reviews Microbiology, 6(2), 132-142.
2. Zipfel P F, et al. (2007). Complement evasion of pathogens: common strategies are shared by diverse organisms. Molecular immunology, 44(16), 3850-3857.