Complement Evasion of Pathogens

Complement Evasion of Pathogens Background

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.

Mechanisms of Complement Evasion

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.

Examples of Complement Evasion Proteins and Their Targets on Host Cells List

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)
Complement-regulator-acquiring protein
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

Complement Evasion of Pathogens References

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.