Streptococcal modulation of cellular invasion via TGF-β1 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-β1 regulates expression of integrins, Fn, and other extracellular matrix proteins, and positively controls the integrin signaling pathway. Therefore, we postulated that TGF-β1 levels could influence streptococcal invasion of mammalian cells. Pretreatment of HEp-2 cells with TGF-β1 increased their capacity to ingest GAS when the bacteria expressed fibronectin-binding proteins (M1 or PrtF1). Western blots revealed significant induction of α5 integrin and Fn expression by HEp-2 cells in response to TGF-β1. Increased ingestion of streptococci by these cells was blocked by a specific inhibitor of the TGF-β1 receptor I and antibodies directed against α5 integrin and Fn, indicating that increased invasion depends on TGF-β1 up-regulation of both the α5 integrin and Fn. The capacity of TGF-β1 to up-regulate integrin expression and intracellular invasion by GAS was reproduced in primary human tonsil fibroblasts, which could be a source of TGF-β1 in chronically infected tonsils. The relationship between TGF-β1 and GAS invasion was strengthened by the observation that TGF-β1 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 α5β1 receptor, enhanced invasion, and increased opportunity for survival and persistence in their human host.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- February 2006
- DOI:
- 10.1073/pnas.0506668103
- Bibcode:
- 2006PNAS..103.2380W
- Keywords:
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- BIOLOGICAL SCIENCES / MICROBIOLOGY