Insight into the molecular basis of pathogen abundance:: Group A Streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells

被引:63
作者
Hoe, NP
Ireland, RM
DeLeo, FR
Gowen, BB
Dorward, DW
Voyich, JM
Liu, M
Burns, EH
Culnan, DM
Bretscher, A
Musser, JM
机构
[1] NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA
[2] NIAID, Rocky Mt Lab, Microscopy Branch, NIH, Hamilton, MT 59840 USA
[3] Drew Univ, Dept Biol, Madison, NJ 07940 USA
[4] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA
关键词
microbiology; serotype M1; epidemic waves; ezrin;
D O I
10.1073/pnas.112039899
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Streptococcal inhibitor of complement (Sic) is a secreted protein made predominantly by serotype M1 Group A Streptococcus (GAS), which contributes to persistence in the mammalian upper respiratory tract and epidemics of human disease. Unexpectedly, an isogenic sic-negative mutant adhered to human epithelial cells significantly better than the wild-type parental strain. Purified Sic inhibited the adherence of a sic negative serotype M1 mutant and of non-Sic-producing GAS strains to human epithelial cells. Sic was rapidly internalized by human epithelial cells, inducing cell flattening and loss of microvilli. Ezrin and moesin, human proteins that functionally link the cytoskeleton to the plasma membrane, were identified as Sic-binding proteins by affinity chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis. Sic colocalized with ezrin inside epithelial cells and bound to the F-actin-binding site region located in the carboxyl terminus of ezrin and moesin. Synthetic peptides corresponding to two regions of Sic had GAS adherence-inhibitory activity equivalent to mature Sic and inhibited binding of Sic to ezrin. In addition, the sic mutant was phagocytosed and killed by human polymorphonuclear leukocytes significantly better than the wild-type strain, and Sic colocalized with ezrin in discrete regions of polymorphonuclear leukocytes. The data suggest that binding of Sic to ezrin alters cellular processes critical for efficient GAS contact, internalization, and killing. Sic enhances bacterial survival by enabling the pathogen to avoid the intracellular environment. This process contributes to the abundance of M1 GAS in human infections and their ability to cause epidemics.
引用
收藏
页码:7646 / 7651
页数:6
相关论文
共 30 条
[1]   Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function [J].
Akesson, P ;
Sjoholm, AG ;
Bjorck, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (02) :1081-1088
[2]   Polarization and interaction of adhesion molecules P-selectin glycoprotein ligand 1 and intercellular adhesion molecule 3 with moesin and ezrin in myeloid cells [J].
Alonso-Lebrero, JL ;
Serrador, JM ;
Domínguez-Jiménez, C ;
Barreiro, O ;
Luque, A ;
del Pozo, MA ;
Snapp, K ;
Kansas, G ;
Schwartz-Albiez, R ;
Furthmayr, H ;
Lozano, F ;
Sánchez-Madrid, F .
BLOOD, 2000, 95 (07) :2413-2419
[3]  
Amieva MR, 1999, J CELL SCI, V112, P111
[4]   Regulation of cortical structure by the ezrin-radixin-moesin protein family [J].
Bretscher, A .
CURRENT OPINION IN CELL BIOLOGY, 1999, 11 (01) :109-116
[5]   Identification of rgg-regulated exoproteins of Streptococcus pyogenes [J].
Chaussee, MS ;
Watson, RO ;
Smoot, JC ;
Musser, JM .
INFECTION AND IMMUNITY, 2001, 69 (02) :822-831
[6]   Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells [J].
Crepaldi, T ;
Gautreau, A ;
Comoglio, PM ;
Louvard, D ;
Arpin, M .
JOURNAL OF CELL BIOLOGY, 1997, 138 (02) :423-434
[7]  
DeLeo FR, 1999, J IMMUNOL, V163, P6732
[8]   High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements [J].
Dombek, PE ;
Cue, D ;
Sedgewick, J ;
Lam, H ;
Ruschkowski, S ;
Finlay, BB ;
Cleary, PP .
MOLECULAR MICROBIOLOGY, 1999, 31 (03) :859-870
[9]   Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes [J].
Fernie-King, BA ;
Seilly, DJ ;
Willers, C ;
Würzner, R ;
Davies, A ;
Lachmann, PJ .
IMMUNOLOGY, 2001, 103 (03) :390-398
[10]  
Fischetti VA, 2000, GRAM-POSITIVE PATHOGENS, P11