Key Points
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The human complement system has a pivotal role in the recognition, opsonization and elimination of microbial intruders. This functionality is maintained by a well-balanced interaction network of serum proteins and cell-surface receptors.
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Over thousands of years of co-evolution, many microorganisms have developed specific complement-evasion strategies to escape the attack of the immune system. Although some of these strategies are highly specific for a single species, others are shared more broadly among bacteria, viruses, fungi and parasites.
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The most prevalent complement-evasion mechanism seems to be the capture of soluble host complement regulators on the microbial surface or the expression of their structural mimics. However, the inactivation of complement components by proteolytic degradation or specific inhibition of essential functional sites is also frequently observed.
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Staphylococcus aureus has a particularly wide and diverse arsenal of complement-evasion proteins, many of which have been discovered only recently. These numerous evasion strategies could contribute to the high virulence of this bacterium.
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Structural biology is an indispensable tool for characterizing the structure and function of complement-evasion proteins. Recent publications of the co-crystal structures of evasion proteins with their human targets have allowed an even deeper insight into the molecular basis of these escape mechanisms.
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The rapid increase in the structural and functional understanding of complement evasion could serve as an important starting point for the development of antimicrobial or complement-targeting therapeutics.
Abstract
The human immune system has developed an elaborate network of cascades for dealing with microbial intruders. Owing to its ability to rapidly recognize and eliminate microorganisms, the complement system is an essential and efficient component of this machinery. However, many pathogenic organisms have found ways to escape the attack of complement through a range of different mechanisms. Recent discoveries in this field have provided important insights into these processes on a molecular level. These vital developments could augment our knowledge of the pathology and treatment of infectious and inflammatory diseases.
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Acknowledgements
This work was supported by National Institutes of Health grants GM-069736, GM-62134, AI-30040, AI-072106 and AI-068730, and by the research incentive funds of the School of Biological Sciences at the University of Missouri-Kansas City.
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John D. Lambris and Brian V. Geisbrecht are the inventors of a patent application that is related to the use of Efb-C as a therapeutic complement inhibitor.
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Glossary
- Pattern-recognition receptor
-
A highly diverse group of soluble and surface-bound proteins that can detect specific molecular surface structures. These receptors are important for discriminating between self and non-self cells (for example, microorganisms) and are, therefore, found in various pathways of the immune system. Prominent examples in the complement system are C1q and mannose-binding lectin.
- Anaphylatoxin
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A small protein fragment (approximately 10 kDa) that is generated during the activation of complement components. C3a and C5a trigger a range of inflammatory and immune-stimulating responses by binding to their receptors (C3aR and C5aR) on various effector cells. The chemotactic activity of C5a is 100-fold higher than that of C3a; no such activities or receptors have so far been described for C4a.
- Toll-like receptor
-
A pattern-recognition receptor that recognizes a range of surface structures on pathogens (for example, proteoglycans and lipopolysaccharides). Toll-like receptors are expressed on most immune cells and their activation and signalling induces numerous inflammatory, innate and adaptive immune responses.
- Short consensus repeat
-
The structural building block of many complement regulators and receptors (for example, factor H and CR1). These β-sheet-rich domains, which are composed of approximately 60 residues, are also found in viral complement-evasion factors and other proteins (for example, selectins, clotting factor XIII B and GABA receptors).
- α-defensin
-
A cationic, cyclic, cysteine-rich peptide of 15–20 amino acids that belongs to a family of antimicrobial peptides. Whereas α-defensins are mainly expressed in mammalian neutrophils, other members of this family have been described in various species within mammals, insects and plants. Although these peptides are thought to primarily disrupt microbial cell walls, they might also act as immunomodulators.
- β-grasp domain
-
A structural fold that consists of anti-parallel β-strands that 'grasp' a single α-helix. Initially described as the central structural element of ubiquitin, this fold was later identified in several other proteins. Despite its small size, it has a wide range of functions and is present in enzymatic, binding and signalling proteins. β-grasp domains are central elements in the structures of a number of bacterial immune-evasion proteins.
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Lambris, J., Ricklin, D. & Geisbrecht, B. Complement evasion by human pathogens. Nat Rev Microbiol 6, 132–142 (2008). https://doi.org/10.1038/nrmicro1824
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DOI: https://doi.org/10.1038/nrmicro1824
