title: Streptococcal modulation of cellular invasion via TGF-beta1 signaling.
abstract: Group A Streptococcus (GAS) and other bacterial pathogens are known to interact with integrins as an initial step in a complex pathway of bacterial ingestion by host cells. Efficient GAS invasion depends on the interaction of bound fibronectin (Fn) with integrins and activation of integrin signaling. TGF-beta1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-beta1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-beta1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of alpha5 integrin and Fn expression by HEp-2 cells in response to TGF-beta1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-beta1 receptor I and antibodies directed against alpha5 integrin and Fn, indicating that increased invasion depends on TGF-beta1 up-regulation of both the alpha5 integrin and Fn. The capacity of TGF-beta1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-beta1 in chronically infected tonsils. The relationship between TGF-beta1 and GAS invasion was strengthened by the observation that TGF-beta1 production was stimulated in GAS-infected primary human tonsil fibroblasts. These findings suggest a mechanism by which GAS induce a cascade of changes in mammalian tissue leading to elevated expression of the alpha5beta1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.
authors.affiliation: Department of Microbiology, University of Minnesota Medical School, 1460 Mayo Memorial Building, MMC 196, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA. beinan@mail.ahc.umn.edu
authors.forename: Beinan
authors.initials: B
authors.lastname: Wang
authors.forename: Shaoying
authors.initials: S
authors.lastname: Li
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Southern
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Cleary
mesh_terms: D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D005347:Fibroblasts / Q000382:microbiology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism*; D014066:Palatine Tonsil / Q000378:metabolism / Q000382:microbiology*; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D005353:Fibronectins; D039482:Integrin alpha5; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1