functional dissection of streptococcus pyogenes m5 protein the hypervariable region is essential for virulence酿脓链球菌m5蛋白质的功能解剖毒性高变区是至关重要的.pdfVIP

Functional Dissection of Streptococcus pyogenes M5 Protein: the Hypervariable Region is Essential for Virulence 1 ˚ 1 1 2 Johan Waldemarsson , Margaretha Stalhammar-Carlemalm , Charlotta Sandin , Francis J. Castellino , Gunnar Lindahl1* 1 Department of Laboratory Medicine, Division of Medical Microbiology, Lund University, Lund, Sweden, 2 W M Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Indiana, United States of America Abstract The surface-localized M protein of Streptococcus pyogenes is a major virulence factor that inhibits phagocytosis, as determined ex vivo. Because little is known about the role of M protein in vivo we analyzed the contribution of different M protein regions to virulence, using the fibrinogen (Fg)-binding M5 protein and a mouse model of acute invasive infection. This model was suitable, because M5 is required for mouse virulence and binds mouse and human Fg equally well, as shown here. Mixed infection experiments with wild type bacteria demonstrated that mutants lacking the N-terminal hypervariable region (HVR) or the Fg-binding B-repeat region were strongly attenuated, while a mutant lacking the conserved C-repeats was only slightly attenuated. Because the HVR of M5 is not required for phagocytosis resistance, our data imply that this HVR plays a major but unknown role during acute infection. The B-repeat region is required for phagocytosis resistance and specifically binds Fg, suggesting that it promotes virulence by binding Fg. However, B-repeat mutants were attenuated even in Fg-deficient mice, implying that