Final Report Summary - MICROTRANS (Microbial translocation across host barriers)
In this project we have decided to combine in vivo, ex vivo and in vitro approaches, with the objective to ascertain the relevance of in vitro findings in vivo, and discover in vivo phenotypes the mechanisms of which will be addressed in vitro in order to better understand host barriers’ biology at the intestinal, blood-brain and materno-fetal interfaces.
MicroTrans project has allowed us to answer following key questions:
1. How invasive pathogens adhere to host barriers? We have shown in an ex vivo intestinal model that Lm interacts with luminally accessible E-cadherin on goblet. We have also shown and published that Lm adheres to the syncytiotrophoblast of the placental barrier in an InlA-Ecad dependent but InlB-Met independent manner. Moreover, we discovered the role of ActA in Lm aggregation, intestinal colonization and carriage.
2. How invasive pathogens cross cell monolayer barriers? To answer this question we have set up a model of crossing epithelial barrier by Lm in an intestinal ex vivo model. We have also deepened our studies on Lm crossing of the intestinal barrier and identified the mechanisms underlying the differences between intestinal and placental barriers crossing, which relies on the basal activity of PI3-K. This kinase is involved in Lm entry and is activated by the InlB-Met interaction. PI3-K activity is high in goblet cells of the intestinal barrier, rendering InlB dispensable for InlA-dependent entry, whereas PI3-K activity is low at the placental barrier, making InlB necessary for InlA-dependent Lm placental invasion.
3. To determine microbial fate and dynamics within the host. We have investigated the liver phase of host infection by Lm. We have shown that Lm induced the death of infected resident macrophages in the liver, and their replacement by activated monocytes, which restored liver homeostasis after Lm elimination. We also investigated Lm biodiversity and discovered hypervirulent strains which harbor a specific set of genes involved in placental and neural tropisms.
4. How host responses influence barrier vulnerability to invasive pathogens? We have studied the host response to Lm infection at the intestinal level (lamina propria and epithelial barrier), the consequence for the bacterial dissemination within the host, as well as on how the microbiota influences host responses at the intestinal level.