Staphylococcal complement evasion by various convertase-blocking molecules

Jongerius, Ilse; Köhl, Jörg; Pandey, Manoj Kumar; Ruyken, Maartje; Kessel, Kok P. M. van; Strijp, Jos A. G. van; Rooijakkers, Suzan H. M.

doi:10.1084/jem.20070818

Cited by 208 publications

(255 citation statements)

References 49 publications

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“…The functions of these exported proteins are unknown, but we speculate that at least some may be virulence factors because proteins exported from bacteria are often toxins or proteins that interfere with the immune system (Beuscher et al, 1995;Emody et al, 2003;Jongerius et al, 2007;Rooijakkers et al, 2005). Several genes involved in transfer of the plasmid were identified, supporting previous in vivo and in vitro observations of horizontal pQC transfer .…”

Section: Discussionsupporting

confidence: 68%

Identification of resistance and virulence factors in an epidemic Enterobacter hormaechei outbreak strain

Paauw

Caspers²,

Hall

et al. 2009

Microbiology

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Bacterial strains differ in their ability to cause hospital outbreaks. Using comparative genomic hybridization, Enterobacter cloacae complex isolates were studied to identify genetic markers specific for Enterobacter cloacae complex outbreak strains. No outbreak-specific genes were found that were common in all investigated outbreak strains. Therefore, the aim of our study was to identify specific genetic markers for an Enterobacter hormaechei outbreak strain (EHOS) that caused a nationwide outbreak in The Netherlands. Most EHOS isolates carried a large conjugative plasmid (pQC) containing genes encoding heavy-metal resistance, mobile elements, pili-associated proteins and exported proteins as well as multiple-resistance genes. Furthermore, the chromosomally encoded high-pathogenicity island (HPI) was highly associated with the EHOS strain. In addition, other DNA fragments were identified that were associated with virulence: three DNA fragments known to be located on a virulence plasmid (pLVPK), as well as phage-and plasmid-related sequences. Also, four DNA fragments encoding putative pili with the most homology to pili of Salmonella enterica were associated with the EHOS. Finally, four DNA fragments encoding putative outer-membrane proteins were negatively associated with the EHOS. In conclusion, resistance and putative virulence genes were identified in the EHOS that may have contributed to increased epidemicity. The high number of genes detected in the EHOS that were related to transferable elements reflects the genomic plasticity of the E. cloacae complex and may explain the emergence of the EHOS in the hospital environment. INTRODUCTIONIn the pre-antibiotic era, isolates of the Enterobacter cloacae complex were not detected in surveys of nosocomial bacteria; they were first described as nosocomial pathogens in the 1970s (Sanders & Sanders, 1997). In 2001, Enterobacter spp. caused 7 % of nosocomial infections in intensive care units in the USA (Jones, 2003;Streit et al., 2004). Therefore, the E. cloacae complex can be considered as an emerging pathogen, of which Enterobacter hormaechei is the most commonly isolated nosocomial pathogen (Delmas et al., 2006;Paauw et al., 2008). A nationwide outbreak occurred with an E. hormaechei outbreak strain (EHOS) in The Netherlands . This strain disseminated throughout hospitals despite adequate implementation of internationally accepted infection-prevention guidelines and caused invasive infections in more than 100 patients (Paauw et al., 2007). Previous studies showed that most EHOS isolates carried the conjugative plasmid pQC, with several complex integrons containing aadB, bla CTX-M-9 and qnrA1 genes that encoded resistance to aminoglycosides and thirdgeneration cephalosporins, and reduced susceptibility to fluoroquinolones, respectively . However, it was also shown that other Enterobacteriaceae including other E. cloacae complex isolates with the pQC did not become highly epidemic like the EHOS (Paauw et al., 2007). Furthermore, of aminoglycoside-susceptible E. cloa...

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Section: Discussionsupporting

confidence: 68%

Identification of resistance and virulence factors in an epidemic Enterobacter hormaechei outbreak strain

Paauw

Caspers²,

Hall

et al. 2009

Microbiology

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“…3a) seem to stabilize the C3 convertases in a non-functional state, thereby efficiently blocking all three pathways 77 . In contrast to Efb and Ehp, SCINs bind only to the assembled C3 convertases [76][77][78] and not to C3 or its fragments. Both the Efb and SCIN families share a high degree of structural similarity with the IgG-binding module of SpA 74,78 (FIG.…”

Section: Suppression Of Complement Amplificationmentioning

confidence: 99%

Complement evasion by human pathogens

2008

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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

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“…Increased antibiotic resistance and a high amount of virulence factors secreted by S. aureus contribute to its emergence as a pathogen. Among these secreted virulence factors are the staphylococcal superantigen-like proteins (SSLs), a family of 14 proteins located on two genomic clusters (2)(3)(4). Recently, we and others identified SSL3 as a potent inhibitor of Tolllike receptor 2 (TLR2) (5,6), an innate immunity receptor that is a dominant factor in immune recognition of S. aureus (7)(8)(9)(10).…”

mentioning

confidence: 99%

“…TLR2 has dual ligand specificity that is determined by its dimerization partner; stimulation by diacyl lipopeptides from Gram-positive bacteria, including S. aureus, induces the formation of heterodimers with TLR6 (13), whereas triacyl lipopeptides from Gram-negative bacteria initiate formation of TLR2-TLR1 dimers (14). The structural basis for lipopeptide specificity was revealed by crystal structures of TLR2-TLR1 and TLR2-TLR6 complexes with their respective lipopeptide analogs Pam 3 CSK 4 and Pam 2 CSK 4 : TLR2 binds two lipid tails in a large hydrophobic pocket, whereas the third lipid tail of triacyl lipopeptides is accommodated by a smaller pocket present in TLR1, but not in TLR6 (15,16).…”

mentioning

confidence: 99%

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

Koymans

Feitsma

Brondijk

et al. 2015

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

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Toll-like receptors (TLRs) are crucial in innate recognition of invading micro-organisms and their subsequent clearance. Bacteria are not passive bystanders and have evolved complex evasion mechanisms. Staphylococcus aureus secretes a potent TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3), which prevents receptor stimulation by pathogen-associated lipopeptides. Here, we present crystal structures of SSL3 and its complex with TLR2. The structure reveals that formation of the specific inhibitory complex is predominantly mediated by hydrophobic contacts between SSL3 and TLR2 and does not involve interaction of TLR2-glycans with the conserved Lewis X binding site of SSL3. In the complex, SSL3 partially covers the entrance to the lipopeptide binding pocket in TLR2, reducing its size by ∼50%. We show that this is sufficient to inhibit binding of agonist Pam 2 CSK 4 effectively, yet allows SSL3 to bind to an already formed TLR2-Pam 2 CSK 4 complex. The binding site of SSL3 overlaps those of TLR2 dimerization partners TLR1 and TLR6 extensively. Combined, our data reveal a robust dual mechanism in which SSL3 interferes with TLR2 activation at two stages: by binding to TLR2, it blocks ligand binding and thus inhibits activation. Second, by interacting with an already formed TLR2-lipopeptide complex, it prevents TLR heterodimerization and downstream signaling.S. aureus | Toll-like receptor | immune evasion | innate immunity | crystal structure

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Staphylococcal complement evasion by various convertase-blocking molecules

Cited by 208 publications

References 49 publications

Identification of resistance and virulence factors in an epidemic Enterobacter hormaechei outbreak strain

Identification of resistance and virulence factors in an epidemic Enterobacter hormaechei outbreak strain

Complement evasion by human pathogens

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

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