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-␤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

In Vivo Demonstration and Quantification of Intracellular Bacillus anthracis in Lung Epithelial Cells

“…For example, uropathogenic E. coli was reported previously to establish quiescent intracellular reservoirs within the urinary bladder epithelium as a mechanism for persistence and a source for recurrent urinary tract infections (27). Group A streptococci appear to upregulate transforming growth factor ␤1 in infected hosts, leading to increased expression of the host cell receptor ␣5␤1 integrin, resulting in enhanced host cell invasion and potentially persistence within the host (34). Anthrax infections can turn latent and become reactivated at a later time.…”

Streptococcus pyogenes serotype-dependent and independent changes in infected HEp-2 epithelial cells

“…The mechanisms of GAS cell adherence and invasion have been extensively studied and reviewed (Courtney et al, 2002;Kreikemeyer et al, 2004;Cleary, 2006). Several studies have investigated the cellular pathways required for the adherence and uptake process phenotypically (Pancholi and Fischetti, 1997;Miettinen et al, 2000;Ozeri et al, 2001;Purushothaman et al, 2003;Wang et al, 2006) and on the global transcriptome scale (Kobayashi et al, 2003;Nakagawa et al, 2004;Klenk et al, 2005). Particularly, the early steps downstream of host cell adherence and internalization determine the fate of the invaded GAS and the infected cell, and are potentially crucial for the disease outcome.…”

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

“…We previously demonstrated that GAS can induce TGF-β1 by cultured human tonsil fibroblasts and that exogenous TGF-β1 up-regulates expression of α5β1 integrins and fibronectin, which are required for internalization of GAS by host cells (4). Among the diverse functions of TGF-β1, this cytokine plays a pivotal role in generation of regulatory T cells (Tregs) and T helper (Th) 17 cells (5-7).…”