Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

Abstract

The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.

Complexity of Complement Resistance Factors Expressed by Acinetobacter baumannii Needed for Survival in Human Serum

“…This discrepancy in human-mouse serum killing could be explained in terms of concentrations of C proteins, which are significantly lower in mouse than in human sera (37) or differences in C regulatory systems between these species (38, 39). The ability to recruit serum C regulatory proteins (CRP) to microbial surfaces is a prominent mechanism of C evasion used by many pathogens (40) and this binding occurs, for most CRPs, in a species-specific manner (41). Overall, the results here highlight the limitations of murine systems for studying serum resistance and virulence of human pathogens, and also show the utility of working within a human system with the genetic and analytic tools used in our study.…”

Novel mechanisms and functions of complement

“…Mechanistically, pathogens can inhibit complement through mimicry or hijacking of complement regulatory proteins, proteolytic inactivation of key complement proteins, or secreting complement inhibitory molecules 9,49 . The list of evasive pathogens and their specific complement targets has greatly increased in recent years and apparently pathogen inhibition of complement can interfere with both innate and adaptive immunity 9,50 . Consequently, key virulence factors involved in complement evasion are currently considered as vaccine targets to promote pathogen susceptibility to complement-dependent host defenses 9 .…”

“…New insights into the mechanisms and locations of complement activation have revealed a new layer of complexity in the biology of complement and its impact on health and disease 7,8 . When dysregulated or overactivated due to host genetic or microbial virulence factors, complement can turn from a homeostatic to a pathological effector that drives various inflammatory disorders and cancer, which reflect the multifaceted nature of complement interactions 3,9 . This Review critically summarizes our updated view of hitherto unanticipated functions of complement and its pervasive role in immunity and disease.…”

Neutrophils and Bacterial Immune Evasion

“…Bacteria can also interfere with complement regulatory proteins as an evasion strategy to limit opsonization. For example, the sequestration of complement regulatory factor H by N. meningitidis impairs complement activation by the alternative pathway which favors bacterial survival [24]. Furthermore, the surface M protein of S. pyogenes impairs the binding of opsonic fragment C3b to the cell surface by inhibiting complement regulatory proteins, such as C4b-binding protein, factor H, and factor H-like protein [25].…”