Complement evasion by human pathogens

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.Evading the manifold attacks of the immune system is a key determinant for the survival of pathogens within their hosts. It is not surprising, therefore, that the coexistence and coevolution of humans and microorganisms has produced a multitude of microbial mechanisms for attenuating or escaping these attacks. As a first line of defence against pathogenic intruders, and a mediator between the innate and adaptive immune responses, the complement system is a particular focus of these evasion strategies. Although this carefully regulated cascade of enzymes, protein complexes and receptors ensures the rapid recognition and elimination of foreign structures, it also offers many sites of interference that can disrupt this balanced network of protein interactions. A detailed understanding of the individual processes and the underlying interactions on a molecular level is essential for describing the mechanisms of infectious diseases and the development of new therapies. Recent discoveries of complement-targeting proteins, the availability of complete microbial genome sequences and advances in experimental methods have propelled this area of research, and provide fascinating insights into complement attack and evasion. Many pathogens seem to have developed parallel routes for escaping complement, and several evasion principles are shared not only among members of the same genus but even among diverse organisms, such as bacteria, viruses, fungi and parasites.In this Review, we will provide a comprehensive over-view and update of the exciting recent developments in this field. After a short introduction that will discuss the diverse role of the complement system in defence, disease and infection, the emphasis will be on the functional and structural aspects of the evasion strategies of human pathogens. Rather than separating them by organism, we classify distinct and common mechanisms for all pathogens based on their mode of action. In light of recent findings, the unique evasion strategies of Staphylococcus

Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor

“…Blocking C5aR also inhibits phagocytosis and intracellular killing of Escherichia coli by human neutrophils (10). The importance of the C5a/C5aR system to antimicrobial defense is underlined by the elaborate strategies evolved by bacteria to avoid the complement system, including blockade of C5a generation and C5aR function (16). However, excess complement activation and C5a generation is also associated with numerous pathologies, including '09 and Unnewher '13 (11, 12).…”

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

“…Overall, host tropism is determined by the immune as well as nonimmune factors (6). Because complement is one of the major innate immune mechanisms that can target cell-free virus and virus-infected cells (7)(8)(9), as well as boost antiviral adaptive immune responses (10,11), Rosengard et al (12) tested the hypothesis that the strict human tropism of variola virus is due, in part, to its ability to evade neutralization by human complement. Their study revealed that the variola-encoded complement regulator called smallpox inhibitor of complement enzymes (SPICE) is ∼100-and 6-fold more potent in inactivating the key human complement proteins C3b (the proteolytically cleaved form of C3) and C4b (the proteolytically cleaved form of C4), respectively, than is vaccinia virus complement control protein (VCP), the complement regulator of vaccinia virus that does not cause disease in immunocompetent humans.…”

Compstatin: A Complement Inhibitor on its Way to Clinical Application

“…However, a similar strategy has been described in case of complement evasion by human pathogens (Lambris et al 2008). In particular, the extracellular fibrinogen-binding protein (Efb) and the related Efbhomologous protein (Ehp) from Staphylococcus aureus have been found to efficiently inhibit complement activation by binding to native C3 and all its fragments that contain the thioester domain (Hammel et al 2007a,b).…”