Abstract
Intestinal Listeria monocytogenes infection is not efficient in mice and this has been attributed to a low affinity interaction between the bacterial surface protein InlA and E-cadherin on murine intestinal epithelial cells. Previous studies using either transgenic mice expressing human E-cadherin or mouse-adapted L. monocytogenes expressing a modified InlA protein (InlAm) with high affinity for murine E-cadherin showed increased efficiency of intragastric infection. However, the large inocula used in these studies disseminated to the spleen and liver rapidly, resulting in a lethal systemic infection that made it difficult to define the natural course of intestinal infection. We describe here a novel mouse model of oral listeriosis that closely mimics all phases of human disease: (1) ingestion of contaminated food, (2) a distinct period of time during which L. monocytogenes colonize only the intestines, (3) varying degrees of systemic spread in susceptible vs. resistant mice, and (4) late stage spread to the brain. Using this natural feeding model, we showed that the type of food, the time of day when feeding occurred, and mouse gender each affected susceptibility to L. monocytogenes infection. Co-infection studies using L. monocytogenes strains that expressed either a high affinity ligand for E-cadherin (InlAm), a low affinity ligand (wild type InlA from Lm EGDe), or no InlA (ΔinlA) showed that InlA was not required to establish intestinal infection in mice. However, expression of InlAm significantly increased bacterial persistence in the underlying lamina propria and greatly enhanced dissemination to the mesenteric lymph nodes. Thus, these studies revealed a previously uncharacterized role for InlA in facilitating systemic spread via the lymphatic system after invasion of the gut mucosa.
Highlights
L. monocytogenes are facultative intracellular bacteria that cause food borne disease in humans ranging in severity from mild, selflimiting gastroenteritis to life-threatening sepsis and meningoencephalitis [1,2,3]
The low infectivity of L. monocytogenes in the gut has long been attributed to a weak interaction between the bacterial surface protein internalin A (InlA) and E-cadherin, a cell adhesion protein expressed on intestinal epithelial cells
Mice are highly resistant to oral L. monocytogenes infection, and the prevailing view has been that a low affinity between the bacterial surface protein InlA and E-cadherin expressed on the gut mucosa was largely responsible for limited invasion of the murine intestines
Summary
L. monocytogenes are facultative intracellular bacteria that cause food borne disease in humans ranging in severity from mild, selflimiting gastroenteritis to life-threatening sepsis and meningoencephalitis [1,2,3]. The low infectivity of L. monocytogenes in the gut has long been attributed to a weak interaction between the bacterial surface protein internalin A (InlA) and E-cadherin, a cell adhesion protein expressed on intestinal epithelial cells. L. monocytogenes can directly invade intestinal epithelial cells in vitro using a ‘‘zipper mechanism’’ triggered by the binding of InlA to E-cadherin [5,6]. Pentecost et al showed that basolaterally expressed E-cadherin was transiently exposed at the tips of intestinal villi as dying cells were extruded from the epithelium, and that L. monocytogenes preferentially bound at the multicellular junctions where this occurred [7]. L. monocytogenes were shown to associate with murine M cells both in vivo and in vitro [11,12,13,14,15] and internalin B (InlB) was implicated in this process [16]. The bacterial adhesins LAP and Vip have been implicated in translocation across the gut mucosa [17,18]
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