the classical and lectin pathways of complement ensure immediate recognition of invading bacteria as nonself .
the c1-complex ( classical pathway ) recognizes bacterium - bound igg and igm while mannose - binding lectins and ficolins ( lectin pathway ) bind bacterial sugar moieties .
s. aureus expresses two surface - anchored proteins that impair igg function ( fig . 
2a ) : staphylococcal protein a ( spa ) and staphylococcal immunoglobulin - binding protein ( sbi ) .
each domain can bind the fc - part of igg , thereby blocking the interaction with fc receptors on neutrophils in vitro [ 10 , 11 ] .
sbi consists of four small domains , of which two ( sbi - i and sbi - ii ) can bind igg .
next to blocking fc - receptor - mediated phagocytosis , sbi has been suggested to block binding of c1q and subsequent activation of the classical pathway . 

are proteins of s. aureus ( red ) and gas ( yellow ) that modulate complement recognition and opsonization .
a to prevent recognition by the classical pathway , s. aureus expresses the surface proteins prota and sbi .
both proteins bind the fc tail of igg preventing its interaction with fcr on neutrophils .
another mechanism to prevent recognition is by inactivating igg , either directly by proteases ides , mac-2 , and speb , or indirectly by sak - activated plasmin .
b there are three ways by which s. aureus and gas modulate opsonization : ( 1 ) c3 cleavage ; directly by speb or indirectly by sak - mediated activated plasmin
( 2 ) convertase modulation ; s. aureus inactivates the c3 convertases by secreting scin , scin - b , scin - c , efb , and ecb .
( 3 ) modulating host regulators ; sbi and the streptococcal m - protein bind the negative convertase regulators ( human fh , fhl1 , c4bp , and cd46 ) while speb cleaves the positive convertase regulator , properdin bacterial evasion of complement recognition ( a ) and opsonization ( b ) .
illustrated are proteins of s. aureus ( red ) and gas ( yellow ) that modulate complement recognition and opsonization .
a to prevent recognition by the classical pathway , s. aureus expresses the surface proteins prota and sbi .
both proteins bind the fc tail of igg preventing its interaction with fcr on neutrophils .
another mechanism to prevent recognition is by inactivating igg , either directly by proteases ides , mac-2 , and speb , or indirectly by sak - activated plasmin .
b there are three ways by which s. aureus and gas modulate opsonization : ( 1 ) c3 cleavage ; directly by speb or indirectly by sak - mediated activated plasmin clfa binds human fi , thereby enhancing c3 cleavage .
( 2 ) convertase modulation ; s. aureus inactivates the c3 convertases by secreting scin , scin - b , scin - c , efb , and ecb .
( 3 ) modulating host regulators ; sbi and the streptococcal m - protein bind the negative convertase regulators ( human fh , fhl1 , c4bp , and cd46 ) while speb cleaves the positive convertase regulator , properdin another strategy to prevent recognition is to eliminate opsonic molecules from the bacterial surface by proteolytic degradation . staphylokinase ( sak ) is a secreted protein that binds and activates surface - bound plasminogen into plasmin , which may enhance bacterial invasion through host tissues .
sak - mediated plasmin deposition on the bacterial surface can cleave igg and c3b and thereby inhibit phagocytosis in vitro .
gas expresses several proteases that directly cleave igg : the endoglycosidase in streptococcus pyogenes ( endos ) specifically hydrolyzes the asparagine - linked glycan in the ch2 domain of igg ; the igg - degrading enzyme of s. pyogenes ( ides or mac-1 ) , mac-2 , and streptococcal pyrogenic exotoxin b ( speb ) all cleave igg in the hinge region [ 14 , 15 ] .
formation of the c3 convertases is elemental for amplification of complement activation and downstream immune responses .
there are three ways by which s. aureus and gas modulate this central step in the complement cascade ( fig . 
2b ) : 
 cleavage of c3 the abundant gas protease speb is , next to cleaving igg , involved in breakdown of c3 .
comparison of wild - type gas and a speb knockout showed that speb blocks neutrophil recruitment to the site of infection and subsequent phagocytosis and bacterial clearance in vivo [ 16 , 17 ] .
the s. aureus surface protein clumping factor a ( clfa ) can bind the human c3b protease factor i ( fi ) , thereby enhancing cleavage of surface - bound c3b into ic3b in vitro . 

direct inactivation of c3 convertases direct inactivation of c3 convertases convertases are the major complement target among s. aureus immune evasion strategies .
staphylococcal complement inhibitor ( scin ) and its homologues scin - b and scin - c are highly effective c3 convertase inhibitors that block conversion of c3 and subsequent phagocytosis and c5a formation in vitro at low concentrations .
the alternative pathway c3 convertase consists of a cofactor ( c3b ) which is loosely bound to the protease subunit ( bb ) .
recent structural studies revealed that the small 10-kd scin protein fixates the convertase conformation and as such hampers a critical rearrangement of the protease subunit bb in relation to substrate c3 [ 20 , 21 ] .
the action of scin on the classical pathway convertase remains to be resolved but seems to be caused by a stabilizing mechanism as well .
extracellular fibrinogen - binding protein ( efb ) and extracellular complement - binding protein ( ecb ) can modulate the alternative pathway convertase by binding to the c3b molecule directly .
the crystal structures of both molecules in complex with the c3d domain of c3 have revealed their exact binding sites [ 23 , 24 ] .
interestingly , since the c3d fragment of c3 is involved in stimulation of adaptive immune responses , it was recently suggested that efb functions as an adaptive immunity modulator as well . 

binding or cleavage of human convertase regulators binding or cleavage of human convertase regulators to protect host tissues from excessive complement activity , humans express complement regulators that downregulate convertase activity .
next to its two igg - binding domains , sbi - iii and iv , it can also bind to c3 .
furthermore , sbi binds the human complement regulators factor h ( fh ) and factor h - related proteins and can form a stable tripartite complex with c3 and fh . altogether
the streptococcal m protein is a multifunctional surface molecule that binds four different human convertase regulators : fh , factor h like-1 ( fhl1 ) , membrane cofactor protein ( cd46 ) , and c4-binding protein ( c4bp ) .
m protein consists of two polypeptide chains configured in an alpha - helical coiled coil complex that is anchored to the cell membrane via its c terminus [ 2830 ] . from the n to the c terminus , the protein comprises four repeat regions : hypervariable ( a ) , variable ( b ) , and conserved ( c and d ) .
depending on the m type , the hypervariable region can bind fh , fhl-1 , and c4bp . by binding these complement regulators ,
m protein limits deposition of c4b and c3b increasing gas resistance to phagocytosis . in vivo studies with strains expressing mutated m protein
finally , speb also digests the positive convertase regulator properdin , making the streptococci more resistant to neutrophil killing in vitro .
in the final step of the complement cascade , the c5 convertases cleave c5 to generate the important chemoattractant c5a that directs neutrophils to the site of infection .
s. aureus and gas use various approaches to evade the c5a - mediated immune responses ( fig .  3 ) .
staphylococcal superantigen - like 7 ( ssl7 ) is a secreted protein that specifically binds to c5   and thereby prevents c5 activation into c5b and c5a in vitro ( j. bestebroer , personal communication ) .
efb and ecb are very potent inhibitors of c5a responses in vitro and in vivo .
these molecules elicit their immune modulating capacity by binding the c3b part of the c5 convertase complex .
scpa cleaves c5a and blocks chemotaxis of phagocytes toward the site of infection . in a mouse pneumonia model
, it was shown that the scpa knockout mutant was less virulent than wild - type gas .
modulation of c5a responses by s. aureus proceeds through inhibition of the c5a receptor ( c5ar ) .
the chemotaxis inhibitory protein of s. aureus ( chips ) is a 14-kd excreted protein that effectively blocks neutrophil recruitment toward c5a in vitro by binding the c5ar with high ( nanomolar ) affinity .
the recent nuclear magnetic resonance ( nmr ) structure of chips in complex with the n terminus of the c5ar showed two sulfated tyrosine ( residues 11 and 14 ) of the c5ar to be essential for the interaction in between the c5ar and the inhibitor chips .
cleavage of c5 also results in formation of c5b , the molecule that initiates the formation of the membrane attack complex ( c5b-9 ) .
mac formation is often monitored in vitro by a so - called hemolytic assay in which erythrocytes ( often sheep or rabbit ) are used as a direct target for complement activation and hemolysis .
the s. aureus proteins scin , efb , ecb , and ssl7 block mac - mediated erythrocyte hemolysis since they inhibit the complement cascade upstream of mac formation .
the highly variable streptococcal inhibitor of complement ( sic ) from gas was found to specifically block formation of the mac by binding to the c5b-7 complex and preventing erythrocyte hemolysis in vitro .
the relevance of mac inhibition by gram - positive bacteria remains unclear since they are naturally protected from lysis via their thick cell wall .
the sic molecule also interacts with several human antimicrobial peptides ( ll-37 , defensins ) , and this might be more relevant for protecting gas from host immunity . 

are proteins of s. aureus ( red ) and gas ( yellow ) that modulate c5-mediated responses .
efb and ecb block the formation of c5 convertases and thereby inhibit c5a and mac generation .
neutrophil influx and phagocytosis are inhibited by chips , which binds the c5ar , and scpa that cleaves c5a .
sic inhibits the formation of the mac , the final step in the complement cascade bacterial evasion of c5-mediated responses .
illustrated are proteins of s. aureus ( red ) and gas ( yellow ) that modulate c5-mediated responses .
efb and ecb block the formation of c5 convertases and thereby inhibit c5a and mac generation .
neutrophil influx and phagocytosis are inhibited by chips , which binds the c5ar , and scpa that cleaves c5a .
bacterial complement modulators have important applications for the treatment of inflammatory diseases where complement is directed against our own cells . per definition , molecules that counteract acute innate immune mechanisms
are anti - inflammatory compounds . as opposed to several bacterial toxins , the high specificity and the mode of action that depends entirely on protein  protein interactions makes these nontoxic proteins suitable anti - inflammatory drugs .
it is tempting to speculate that these molecules could be used as injectables in acute inflammatory disorders .
however , since these molecules are derived from common human pathogens , pre - existing antibodies severely complicate this approach . furthermore , a number of the described molecules appear to be human - specific which complicates functional studies in vivo [ 19 , 44 , 45 ] however
, the immunological molecules that are attacked by these factors might prove to be the essential targets to tackle in anti - inflammatory therapy .
we feel that the bacterial products could be used as an indicator of the  achilles heel  of the human immune system  almost at the atomic level .
especially , since the 3-d structures of a number of molecules in context with their target are now elucidated in several crystallographic and nmr studies [ 19 , 20 , 25 , 40 , 46 ] , this opens new possibilities for smart design of small - molecule therapeutics .
thus , we can copy these evolutionary - designed molecules to counteract the detrimental effects of complement activation in inflammatory disease states .
next to their potential as anti - inflammatory compounds , we believe that targeting of complement evasion molecules should be included in future strategies to fight bacterial infections . the evasion molecules described above not only suppress natural immunity during an infection but also hamper the current attempts to create effective vaccines .
the efficacy of vaccines is held back by the existing bacterial immune evasion strategies since they prevent neutrophils or complement to reach the site of infection .
even with sufficient opsonic or bactericidal antibodies on the bacterium , nothing will happen if the innate immune effectors are absent .
since immune evasion molecules are essentially vaccine evasion molecules , we propose that these molecules should be specifically targeted in the vaccine .
alternatively , we could think of ways to neutralize these molecules and use that in novel strategies to fight infectious diseases .
in fact , we propose to inhibit the inhibitor and thereby decrease the advantage of the bacterium over the host .
so , taken together , the smart attack of the bacteria on our complement system might hold clues for future drugs in both inflammatory as well as infectious diseases . in this way , we could turn this powerful escape mechanism into our own advantage .
 the plasma proteins of the complement system are essential in the innate immune response against bacteria . 
 complement labels bacteria with opsonins to support phagocytosis and generates chemoattractants to attract phagocytes to the site of infection . in turn 
 , bacterial human pathogens have evolved different strategies to specifically impair the complement response . here , we review the large arsenal of complement inhibitors produced by the gram - positive pathogens staphylococcus aureus and group a streptococcus . 
 we discuss how these bacterial molecules provide us with new tools to treat both infectious and inflammatory disease conditions in humans . 
Modulation of complement recognition and activation
Modulation of complement amplification
Modulation of the complement effector functions: inhibiting C5 activation and neutrophil migration
Complement evasion molecules as tools and targets in therapy