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.

Keywords: bacteria; complement; complement regulatory proteins; immune evasion of bacteria; vaccine development.

Figure 1

Membrane bound complement regulatory proteins. (A) Membrane bound complement regulatory receptors DAF, MCP, CR1, and CD59. The SCRs important for the binding of complement targets are indicated. (B) DAF, depicted in the upper membrane, accelerates the decay of C3 convertases and prevents formation of new C3 convertases. MCP, depicted next to DAF, acts as a cofactor for FI, which cleaves C3b and C4b. On the lower membrane, CR1 is shown which acts as a cofactor for FI mediating cleavage of C3b as well as C4b (not depicted in this picture). Lastly, CD59 binds to C5b-8 and C5b-9 preventing the formation of the MAC. Figure was produced using Servier Medical Art.

Figure 2

Host fluid phase complement regulatory proteins. (A) Fluid regulatory protein C1-inh prevents complement activation by binding to C1s and C1r (and MASP-1 and MASP-2, not depicted here) preventing the cleavage of C4 and C2 and hence the formation of the CP and LP C3 convertase. (B) C4BP binding to C4b mediates dissociation of the CP and LP C3 and C5 convertases. Furthermore, C4BP binding to C4b increases proteolytic cleavage of C4b by FI. (C) The main AP fluid regulator, FH, binds to GAG on the cellular membrane and mediates dissociation of the AP C3 convertases by binding C3b causing dissociation of Bb from the C3 convertase. Furthermore, FI is recruited leading to the proteolytic cleavage of C3b. (D) The last fluid phase inhibitor is Vn which binds to integrins in the host membrane. Vn binds the metastable membrane binding site of C5b-7 preventing the formation of the MAC. Figure was produced using Servier Medical Art.

Figure 3

Complement evasion strategies of bacteria. Complement evasion strategies of bacteria can be divided into four different groups. (A) The expression of proteins that mimic host structures like the CD59-like protein of B. burgdorferi which inhibits MAC formation. (B) The secretion of bacterial proteases like PaE and PaAP expressed by P. aeruginosa which cleave C3. S. pyogenes SpeB cleaves C3, properdin and IgG. (C) Inhibition of TLR2 by F. tularensis. This bacterium exploits being opsonized by C3b to engage CR3 on macrophages to facilitate entry as well as to induce both inside-out as well as outside-in signaling of CR3 resulting in decreased TLR2 activity. (D) The secretion of small bacterial proteins with complement inhibitory properties as is shown for S. aureus. This pathogen secretes Ecb and Efb that bind to the C3d domain of C3b and thereby inhibit the formation of the C3b containing CP and LP C5 convertase as well as inhibit the formation of the AP C3 convertase by stabilizing the binding of FB to C3b preventing cleavage of FB into Bb. Furthermore, SSL7 is secreted which binds C5 and IgA inhibiting the generation of C5a and thus subsequent neutrophil infiltration. (E) The recruitment of fluid phase complement regulatory proteins C1-inh, C4BP, FH, and Vn to the bacterial membrane which will be discussed in this review. Figure was produced using Servier Medical Art.

Figure 4

C4BP recruitment by bacterial pathogens. (A) PspC4.4 of S. pneumoniae recruits C4BP to the bacterial surface resulting in the decay of CP and LP C3 convertase and proteolytic cleavage of C4b. This subsequently inhibits formation of the MAC as well as decreases phagocytic uptake of the bacteria due to the inhibition of C3b deposition and C5a generation. (B) Multiple bacteria can bind the α-chain of C4BP at different sites as indicated by the gray rectangles. SCRs 1-3 of the α-chain mediate the interaction with C4b. Figure was produced using Servier Medical Art.

Figure 5

FH binding by bacterial pathogens. (A) One example of a FH binding bacterial protein is the surface protein CspZ of B. burgdorferi. CspZ interacts with SCR 20 of FH recruiting this AP regulator to the bacterial surface resulting in the decay of the AP C3 convertase and proteolytic degradation of C3b into iC3b and C3d. This subsequently inhibits formation of the MAC as well as decreases phagocytic uptake of the bacteria due to the inhibition of C3b deposition and C5a generation. (B) Multiple bacteria can bind FH at different sites as indicated by the gray rectangles. SCRs 1-4 mediate the interaction with C3b and SCRs 19-20 are involved in recognizing self from non-self. Figure was produced using Servier Medical Art.

Figure 6

Vn binding by bacterial pathogens. (A) Hsf of H. influenzae binds to the HBD3 of Vn. By recruiting Vn to the bacterial surface, H. influenzae inhibits formation of the MAC. (B) Multiple bacteria can bind Vn at different sites as indicated by the gray rectangles. Bacterial pathogens either interact with Vn's connecting region or with the C-terminal HBD3. Figure was produced using Servier Medical Art.