Abstract
BackgroundThe bacterial surface protein internalin (InlA) is a major virulence factor of the food-born pathogen Listeria monocytogenes. It plays a critical role in the bacteria crossing the host intestinal barrier by a species-specific interaction with the cell adhesion molecule E-cadherin. In mice, the interaction of InlA with murine E-cadherin is impaired due to sequence-specific binding incompatibilities. We have previously used the approach of ‘murinisation’ to establish an oral listeriosis infection model in mice by exchanging two amino acid residues in InlA. This dramatically increases binding to mouse E-cadherin. In the present study, we have used bioluminescent murinised and non-murinised Listeria strains to examine the spatiotemporal dissemination of Listeria in four diverse mouse genetic backgrounds after oral inoculation.ResultsThe murinised Listeria monocytogenes strain showed enhanced invasiveness and induced more severe infections in all four investigated mouse inbred strains compared to the non-murinised Listeria strain. We identified C57BL/6J mice as being most resistant to orally acquired listeriosis whereas C3HeB/FeJ, A/J and BALB/cJ mice were found to be most susceptible to infection. This was reflected in faster kinetics of Listeria dissemination, higher bacterial loads in internal organs, and elevated serum levels of IL-6, IFN-γ, TNF-α and CCL2 in the susceptible strains as compared to the resistant C57BL/6J strain. Importantly, murinisation of InlA did not cause enhanced invasion of Listeria monocytogenes into the brain.ConclusionMurinised Listeria are able to efficiently cross the intestinal barrier in mice from diverse genetic backgrounds. However, expression of murinized InlA does not enhance listerial brain invasion suggesting that crossing of the blood brain barrier and crossing of the intestinal epithelium are achieved by Listeria monocytogenes through different molecular mechanisms.
Highlights
The bacterial surface protein internalin (InlA) is a major virulence factor of the food-born pathogen Listeria monocytogenes
We report here that infection with murinised Listeria resulted in earlier onset of listeriosis compared to infections with the non-murinised Listeria strain in different mouse genetic backgrounds
Dynamics of Lmo-Internalin A (InlA)-mur-lux and Lmo-EGD-lux dissemination visualized by bioluminescent in vivo imaging (BLI) To compare the dissemination dynamics of the murinised and wildtype L. monocytogenes strains in different inbred genetic backgrounds, C57BL/6J, C3HeB/FeJ, A/J, and BALB/cJ female mice (n = 10) were intragastrically infected with 5 × 109 colony forming units (CFU) of either Lmo-InlA-mur-lux or Lmo-EGD-lux
Summary
The bacterial surface protein internalin (InlA) is a major virulence factor of the food-born pathogen Listeria monocytogenes It plays a critical role in the bacteria crossing the host intestinal barrier by a species-specific interaction with the cell adhesion molecule E-cadherin. InlA induces listerial internalisation into intestinal epithelial cells by binding to the N-terminal domain of the human E-cadherin (Cdh1) cell adhesion protein [10] It can interact with Cdh from guinea pig, rabbit and gerbil but fails to bind to the corresponding domain of the murine and rat Cdh. A major breakthrough was the generation of a transgenic mouse line which expresses the human E-cadherin (CDH1) gene under the control of the enterocyte specific promoter of intestinal fattyacid-binding protein This mouse model demonstrated for the first time that the interaction of InlA with Cdh is crucial for listerial intestinal invasion in vivo [15]. The ubiquitous expression of a ‘humanized’ Cdh in this mouse allows the investigation of InlA-Cdh and InlB-Met interactions in vivo
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