Engagement of CD46 and alpha5beta1 integrin by group A streptococci is required for efficient invasion of epithelial cells.
Membrane cofactor protein (MCP or CD46), a widely distributed complement regulatory human protein, is a cell surface receptor for many pathogens including group A streptococci (GAS). The surface M protein of GAS binds CD46 and mediates GAS adherence to keratinocytes. In the present study, we studied the role of CD46 in GAS invasion of human lung epithelial cells, A549. Anti-CD46 antibody which specifically blocks the domain to which M protein binds inhibited adherence to and invasion of A549 cells by GAS. Moreover, downregulation of CD46 expression on A549 by RNA interference resulted in reduced invasion of these cells by GAS. A mutant form of CD46 with a deletion in the cytoplasmic domain was overexpressed in A549 cells, which resulted in partial inhibition of invasion. This indicates that the cytoplasmic tail is required for CD46 to promote invasion by GAS. Invasion assays with Lactococcus lactis that express M protein demonstrated the dependence of CD46-promoted invasion on interaction with M protein. In addition, CD46-mediated invasion was also found to be dependent on the extracellular matrix protein fibronectin.
Rezcallah
Myrna S
MS
Department of Microbiology, University of Minnesota, Minneapolis, 55455, USA.
Hodges
Kimberly
K
Gill
Darcy B
DB
Atkinson
John P
JP
Wang
Beinan
B
Cleary
P Patrick
PP
D000942:Antigens, Bacterial / Q000378:metabolism; D001422:Bacterial Adhesion; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039081:Integrin alpha5beta1 / Q000096:biosynthesis*; D013294:Lactococcus lactis / Q000378:metabolism; D051916:Membrane Cofactor Protein / Q000096:biosynthesis*; D034622:RNA Interference; D013297:Streptococcus pyogenes / Q000472:pathogenicity / Q000502:physiology*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D051916:Membrane Cofactor Protein; C014689:streptococcal M protein