Listeria monocytogenes Internalin B Activates Junctional Endocytosis to Accelerate Intestinal Invasion

Listeria monocytogenes (Lm) uses InlA to invade the tips of the intestinal villi, a location at which cell extrusion generates a transient defect in epithelial polarity that exposes the receptor for InlA, E-cadherin, on the cell surface. As the dying cell is removed from the epithelium, the surrounding cells reorganize to form a multicellular junction (MCJ) that Lm exploits to find its basolateral receptor and invade. By examining individual infected villi using 3D-confocal imaging, we uncovered a novel role for the second major invasin, InlB, during invasion of the intestine. We infected mice intragastrically with isogenic strains of Lm that express or lack InlB and that have a modified InlA capable of binding murine E-cadherin and found that Lm lacking InlB invade the same number of villi but have decreased numbers of bacteria within each infected villus tip. We studied the mechanism of InlB action at the MCJs of polarized MDCK monolayers and find that InlB does not act as an adhesin, but instead accelerates bacterial internalization after attachment. InlB locally activates its receptor, c-Met, and increases endocytosis of junctional components, including E-cadherin. We show that MCJs are naturally more endocytic than other sites of the apical membrane, that endocytosis and Lm invasion of MCJs depends on functional dynamin, and that c-Met activation by soluble InlB or hepatocyte growth factor (HGF) increases MCJ endocytosis. Also, in vivo, InlB applied through the intestinal lumen increases endocytosis at the villus tips. Our findings demonstrate a two-step mechanism of synergy between Lm's invasins: InlA provides the specificity of Lm adhesion to MCJs at the villus tips and InlB locally activates c-Met to accelerate junctional endocytosis and bacterial invasion of the intestine

Do regulations encourage innovation? The case of energy efficiency in housing

This paper addresses the impact of building regulations on constraints and drivers for innovation. It seeks to clarify whether a supposed shift from prescriptive to performance-based regulations has improved the environment for technical innovation in energy efficient housing in Britain. We argue that when ‘performance-based’ building regulations are treated as static sets of technical requirements, their effect is similar to more traditional prescriptive forms of regulation. A more progressive approach is possible in which regulations can be used as part of a portfolio of policies aimed at improving performance. In this mode, functional performance specifications can stimulate systemic innovation. A flexible ‘performance-based’ form of standard could provide firms with the freedom, market incentive and institutional frameworks within which to innovate. The process itself could lead to information sharing and cooperation but for this to be achieved, competitiveness and regulatory policies need to be co-ordinated better. Regulatory objectives and mechanisms for achieving them need to match. Regulations need to accommodate technical change at different levels in the production process, including new product development and systems integration