Browsing by Subject "Collagen-binding MSCRAMMs"
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Item Complement Evasion by S. aureus Surface Proteins(2014-08-28) Kang, MingsongThe complement system, a major component of the innate immunity, is critical for combating microbial infections. It can be activated by three distinct pathways: the classical pathway, the lectin pathway and the alternative pathway. Activation of the complement system results in opsonization of pathogens, recruitment of phagocytes, and lysis of bacterial cells. However, successful pathogenic bacteria have evolved strategies to manipulate the complement system, aiming to tip the balance in favor of the bacteria. Staphylococcus aureus is an important human pathogen causing more deaths than that of HIV in the United States. It can cause diseases ranging from minor skin infections to life threatening diseases. While most complement evasion molecules from S. aureus are secreted proteins and are well characterized, little is known about the effect of surface-anchored S. aureus proteins on complement activity. This study aims to bridge this gap and investigate the role of S. aureus surface proteins in complement evasion. S. aureus expresses different kinds of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) that interact with host extracellular matrix (ECM) proteins. My studies mainly focus on collagen-binding MSCRAMM Can and fibrinogen-binding MSCRAMM Bbq/S drE using the hemolysis and the C4b deposition ELISA-type essay to analyze complement activation and a serial biochemical and immunological approaches such as ELISA, biacore and IP assays to investigate the binding and inhibition mechanisms. I found that Cna specifically interacts with the collagen-like domain of Cl q. This binding disturbs Cl complex assembly and causes decrease in Cl binding to the immune complex. Moreover, animal studies revealed that Cl q knockout mice are resistant to Cna-expressing S.aureus infections and have much less bacterial burdens in liver, compared to that of wild type mice, suggesting that this interaction enhances S.aureus infection and dissemination. Furthermore, my study also revealed that Bbp/S drE blocks all three complement pathways and the binding of Bbp to C3c fragment of C3b blocks the formation of the AP C3 convertase by interfering with the cleavage of factor B. In summary, I reported that several MSCRAMMs from S.aureus not only bind to ECM proteins, but are also complement inhibitors that would benefit S.aureus infections.