Mechanism of action of the group A streptococcal C5a inactivator.

Wexler, D E; Chenoweth, Dennis E.; Cleary, P. Patrick

doi:10.1073/pnas.82.23.8144

Cited by 155 publications

(144 citation statements)

References 21 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…In contrast to S. aureus, other Gram-positive bacteria like Group A streptococci rather use proteases to protect themselves from complement attack (43,44). For example, streptococcal cysteine protease SpeB degrades C3 to inhibit bacterial clearance (45), whereas the streptococcal cellassociated peptidase ScpA cleaves C5a to inhibit neutrophil chemotaxis (46). In this study, we describe that S. aureus also uses its proteases to dampen the complement response.…”

Section: Discussionmentioning

confidence: 95%

Staphylococcus aureus Metalloprotease Aureolysin Cleaves Complement C3 To Mediate Immune Evasion

Laarman

Ruyken

Malone

et al. 2011

The Journal of Immunology

176

126

View full text Add to dashboard Cite

Complement is one of the first host defense barriers against bacteria. Activated complement attracts neutrophils to the site of infection and opsonizes bacteria to facilitate phagocytosis. The human pathogen Staphylococcus aureus has successfully developed ways to evade the complement system, for example by secretion of specific complement inhibitors. However, the influence of S. aureus proteases on the host complement system is still poorly understood. In this study, we identify the metalloprotease aureolysin as a potent complement inhibitor. Aureolysin effectively inhibits phagocytosis and killing of bacteria by neutrophils. Furthermore, we show that aureolysin inhibits the deposition of C3b on bacterial surfaces and the release of the chemoattractant C5a. Cleavage analyses show that aureolysin cleaves the central complement protein C3. Strikingly, there was a clear difference between the cleavages of C3 in serum versus purified conditions. Aureolysin cleaves purified C3 specifically in the α-chain, close to the C3 convertase cleavage site, yielding active C3a and C3b. However, in serum we observe that the aureolysin-generated C3b is further degraded by host factors. We pinpointed these factors to be factor H and factor I. Using an aureolysin mutant in S. aureus USA300, we show that aureolysin is essential and sufficient for C3 cleavage by bacterial supernatant. In short, aureolysin acts in synergy with host regulators to inactivate C3 thereby effectively dampening the host immune response.

show abstract

Section: Discussionmentioning

confidence: 95%

Staphylococcus aureus Metalloprotease Aureolysin Cleaves Complement C3 To Mediate Immune Evasion

Laarman

Ruyken

Malone

et al. 2011

The Journal of Immunology

176

126

View full text Add to dashboard Cite

show abstract

“…First, they can inhibit effector functions of complement activation. For example, bacterial capsules are thought to act by preventing the insertion of the MAC into the outer membrane (46,47), while Streptococcus pyogenes secretes a protease that directly cleaves C5, the first component of the MAC (48,49). Alternatively, pathogens can recruit negative regulators of the host complement system to their surface.…”

Section: Discussionmentioning

confidence: 99%

Functional Significance of Factor H Binding toNeisseria meningitidis

Schneider

Exley

Chan

et al. 2006

The Journal of Immunology

220

197

View full text Add to dashboard Cite

Neisseria meningitidis is an important cause of septicemia and meningitis. To cause disease, the bacterium must successfully survive in the bloodstream where it has to avoid being killed by host innate immune mechanisms, particularly the complement system. A number of pathogenic microbes bind factor H (fH), the negative regulator of the alternative pathway of complement activation, to promote their survival in vivo. In this study, we show that N. meningitidis binds fH to its surface. Binding to serogroups A, B, and C N. meningitidis strains was detected by FACS and Far Western blot analysis, and occurred in the absence of other serum factors such as C3b. Unlike Neisseria gonorrhoeae, binding of fH to N. meningitidis was independent of sialic acid on the bacterium, either as a component of its LPS or its capsule. Characterization of the major fH binding partner demonstrated that it is a 33-kDa protein; examination of insertion mutants showed that porins A and B, outer membrane porins expressed by N. meningitidis, do not contribute significantly to fH binding. We examined the physiological consequences of fH bound to the bacterial surface. We found that fH retains its activity as a cofactor of factor I when bound to the bacterium and contributes to the ability of N. meningitidis to avoid complement-mediated killing in the presence of human serum. Therefore, the recruitment of fH provides another mechanism by which this important human pathogen evades host innate immunity.

show abstract

“…Proteolytic cleavage of complement components by bacterial proteases is a mechanism used by many human pathogens. Examples are streptococcal cysteine protease SpeB, which degrades C3 to inhibit bacterial clearance (25), the streptococcal cell-associated peptidase ScpA, which cleaves C5a to inhibit neutrophil chemotaxis (26), GelE of Enterococcus faecalis (27) and aureolysin of Staphylococcus aureus, which cleave C3 (28), EspP of enterohemorrhagic E. coli, which cleaves C3 and C5 to impair complement activation (29), and PgtE of Salmonella enterica, which proteolytically cleaves C3b, C4b, and C5 to enhance bacterial resistance to human serum (30).…”

Section: Discussionmentioning

confidence: 99%

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Tordello

Vacca

Ram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The complement system is a crucial component of the innate immune response against invading bacterial pathogens. The human pathogen Neisseria meningitidis (Nm) is known to possess several mechanisms to evade the complement system, including binding to complement inhibitors. In this study, we describe an additional mechanism used by Nm to evade the complement system and survive in human blood. Using an isogenic NalP deletion mutant and NalP complementing strains, we show that the autotransporter protease NalP cleaves C3, the central component of the complement cascade. The cleavage occurs 4 aa upstream from the natural C3 cleavage site and produces shorter C3a-like and longer C3b-like fragments. The C3b-like fragment is degraded in the presence of the complement regulators (factors H and I), and this degradation results in lower deposition of C3b on the bacterial surface. We conclude that NalP is an important factor to increase the survival of Nm in human serum.serum resistance | immune evasion

show abstract

Mechanism of action of the group A streptococcal C5a inactivator.

Cited by 155 publications

References 21 publications

Staphylococcus aureus Metalloprotease Aureolysin Cleaves Complement C3 To Mediate Immune Evasion

Staphylococcus aureus Metalloprotease Aureolysin Cleaves Complement C3 To Mediate Immune Evasion

Functional Significance of Factor H Binding toNeisseria meningitidis

Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum

Contact Info

Product

Resources

About