Abstract
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths. S. flexneri pathogenic properties rely on its ability to invade epithelial cells and spread from cell to cell within the colonic epithelium. This dissemination process relies on actin-based motility in the cytosol of infected cells and formation of membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the pathogen escapes, thereby achieving cell-to-cell spread. S. flexneri dissemination is facilitated by the type 3 secretion system (T3SS) through poorly understood mechanisms. Here, we show that the T3SS effector IpgD facilitates the resolution of membrane protrusions into DMVs during S. flexneri dissemination. The phosphatidylinositol 4-phosphatase activity of IpgD decreases PtdIns(4,5)P2 levels in membrane protrusions, thereby counteracting de novo cortical actin formation in protrusions, a process that restricts the resolution of protrusions into DMVs. Finally, using an infant rabbit model of shigellosis, we show that IpgD is required for efficient cell-to-cell spread in vivo and contributes to the severity of dysentery.
Highlights
The intestinal pathogen Shigella flexneri is the causative agent of bacillary dysentery [1]
Cell-to-cell spread relies on the formation of membrane protrusions that project into adjacent cells and resolve into vacuoles
We show that S. flexneri employs the phosphatidylinositol phosphatase activity of the type 3 secretion system (T3SS) effector protein IpgD to manipulate phosphoinositides in the protrusion membrane
Summary
The intestinal pathogen Shigella flexneri is the causative agent of bacillary dysentery [1]. The development of in vitro tissue culture systems [6] and genetic approaches [7] led to the discovery that S. flexneri invasion properties rely on the type 3 secretion system (T3SS) [8], which delivers a panel of effector proteins that manipulate the actin cytoskeleton, leading to bacterial engulfment into primary vacuoles [9]. As they escape primary vacuoles, bacteria exploit the actin cytoskeleton to display actin-based motility in the cytosol of infected cells [10]. The resolution of these protrusions leads to the formation of double membrane vacuoles [17,18], from which the pathogen escapes by deploying its T3SS and specific effector proteins [19,20,21]
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