Insight into the molecular basis of pathogen abundance: group A Streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells.
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.
Hoe
Nancy P
NP
Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, USA.
Ireland
Robin M
RM
DeLeo
Frank R
FR
Gowen
Brian B
BB
Dorward
David W
DW
Voyich
Jovanka M
JM
Liu
Mengyao
M
Burns
Eugene H
EH
Culnan
Derek M
DM
Bretscher
Anthony
A
Musser
James M
JM
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000907:Antibodies, Bacterial / Q000494:pharmacology; D001422:Bacterial Adhesion / Q000187:drug effects / Q000502:physiology*; D001665:Binding Sites; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D003598:Cytoskeletal Proteins; D004847:Epithelial Cells / Q000382:microbiology; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000382:microbiology; D010750:Phosphoproteins / Q000737:chemistry / Q000494:pharmacology; D012141:Respiratory Tract Infections / Q000382:microbiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012703:Serotyping; D013290:Streptococcal Infections / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000145:classification / Q000472:pathogenicity*; D000099149:Ezrin
D000199:Actins; D000907:Antibodies, Bacterial; D003169:Complement Inactivator Proteins; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000099149:Ezrin; C071058:moesin