A nonpetide integrin antagonist can inhibit epithelial cell ingestion of
            <i>Streptococcus pyogenes</i>
            by blocking formation of integrin α5β1-fibronectin-M1 protein complexes

Cue, David; Southern, Šárka O.; Southern, Peter J.; Prabhakar, Jadhar; Lorelli, William; Smallheer, Joanne M.; Mousa, Shaker A.; Cleary, P. Patrick

doi:10.1073/pnas.050587897

Cited by 95 publications

(81 citation statements)

References 32 publications

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“…The capacity to bind Fn renders these bacteria capable of employing integrins as receptors for efficient internalization. Extensive studies established that ␣5␤1 integrin is the primary receptor for M1-mediated (8,34) and PrtF1-mediated GAS invasion of epithelial cells (9,11). Integrin signaling required for Streptococcus internalization has only recently been investigated (10,12,35).…”

Section: Discussionmentioning

confidence: 99%

“…or lymphocytes associated with small numbers of streptococci within this tissue are chronic sources of TGF-␤1, which up-regulates integrin receptors on the tonsil epithelium and increases susceptibility to infection. In earlier studies, we reported the potential of GAS to invade human primary tonsil epithelial cells (PHTF) in vitro (8). As we have continued to work with tonsil explants, we have identified considerable variability in the populations of primary cells that can be grown out (30).…”

Section: Tgf-␤1 Enhances Expression Of ␣5 Integrin and Invasion Of Phtfmentioning

confidence: 99%

“…Engagement of ␣5␤1 integrin with Fn bound to these proteins initiates phosphoinositide 3-kinase (10,12) and integrin-linked kinase-dependent intracellular signals that induce cytoskeletal rearrangement and ingestion of streptococci (10). Most studies of invasion have used immortalized human cell lines; however, a connection between ␣5␤1 integrin and Fn was also confirmed when GAS invasion was studied in primary cultures of human tonsillar cells (8).…”

mentioning

confidence: 99%

“…GAS invasion of immortalized epithelial cells is highly efficient (10-60% of inoculum) in the presence of fibronectin (Fn) and this invasion is critically dependent on the interaction of bound Fn with cellular integrins (6)(7)(8). The bacteria can express several invasins, but the Fn-binding proteins (FnBPs), M1 and PrtF1͞Sfb1, have been studied in most detail (9)(10)(11).…”

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confidence: 99%

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Streptococcal modulation of cellular invasion via TGF-β1 signaling

Wang

Southern

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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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-␤1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-␤1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-␤1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of ␣5 integrin and Fn expression by HEp-2 cells in response to TGF-␤1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-␤1 receptor I and antibodies directed against ␣5 integrin and Fn, indicating that increased invasion depends on TGF-␤1 up-regulation of both the ␣5 integrin and Fn. The capacity of TGF-␤1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-␤1 in chronically infected tonsils. The relationship between TGF-␤1 and GAS invasion was strengthened by the observation that TGF-␤1 production was stimulated in GASinfected 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 ␣5␤1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.integrin ͉ fibronectin ͉ fibronectin binding protein ͉ tonsils

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Section: Discussionmentioning

confidence: 99%

Section: Tgf-␤1 Enhances Expression Of ␣5 Integrin and Invasion Of Phtfmentioning

confidence: 99%

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confidence: 99%

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Streptococcal modulation of cellular invasion via TGF-β1 signaling

Wang

Southern

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…A model in which interactions with the N-terminal modules cause a conformational change that opens up the integrin-binding site, rather than vice versa, has a precedent in studies of bacteria-FN interactions (Ozeri et al, 1998). In the case of Streptococcus pyogenes, binding of protein F1 to the N-terminal region of FN enables cellular uptake of bacteria-FN complexes by a process that is inhibitable by RGD peptides, involves integrins and likely contributes to bacterial virulence (Cue et al, 2000;Nyberg et al, 2004;Ozeri et al, 1998). Thus, cellular uptake of S. pyogenes may represent a subversion of the mechanism whereby binding via the N-terminal region of FN exposes the cryptic integrinbinding type III 10 repeat.…”

Section: Introductionmentioning

confidence: 99%

The N-terminal 70-kDa fragment of fibronectin binds to cell surface fibronectin assembly sites in the absence of intact fibronectin

2006

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Binding of the N-terminal 70-kDa (70K) fragment of fibronectin to fibroblasts blocks assembly of intact fibronectin and is an accurate indicator of the ability of various agents to enhance or inhibit fibronectin assembly. Such binding is widely thought to be to already assembled fibronectin. We evaluated this hypothesis with fibronectin-null mouse fibroblasts plated on laminin-1 in the absence of intact fibronectin. As a proteolytic fragment or recombinant protein, 70K bound fibronectin-null cells specifically in linear arrays that extended outwards from the periphery of spread cells. At early time points, these arrays were similar to those formed by intact fibronectin. 70K arrays formed within 5min following ligand addition at concentrations as low as 5nM, indicating rapid and high affinity binding. Bound 70K was extractable with Triton X-100 or deoxycholate but became insoluble when cross-linked with a membrane-impermeable agent into large SDS-stable complexes. Intact fibronectin, in contrast, became progressively non-extractable in the absence of cross-linking. The detergent-resistant arrays of cross-linked 70K localized to tips of cellular extensions and partially overlapped with α 6 and β 1 integrin subunits at the base of the extensions. α 5 did not localize with 70K arrays, but became progressively co-localized with assemblies of intact fibronectin over time. These results support a model in which the 70-kDa region of fibronectin binds to linearly arrayed cell surface molecules of adherent cells to initiate assembly, display of the arrays is controlled by the integrin that mediates adhesion, and fibronectin-binding integrins promote fibronectinfibronectin interactions during progression of assembly.

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