Early innate response of intestinal epithelial cells is the first line defense against enteric pathogens. Toxoplasma gondii infections acquired naturally via the peroral route, encounter intestinal epithelial cells early post-infection. Although the population structure of T. gondii is known to be highly clonal, clinical strains of T. gondii have been classified into three genotypes based on their virulence. In this study we investigated whether human intestinal epithelial cell immune response to T. gondii is virulence dependent. We demonstrated distinct virulence of the three T. gondii genotype strains evaluated in human intestinal epithelial cells by their capacity to replicate and induce host cell cytotoxicity. The early host innate mechanisms such as activation of signaling pathways and induction of innate effectors were likewise differentially elicited by the three T. gondii strains. Low levels of TLR dependent NF-kB activation and a failure to rapidly up-regulate innate cytokine and chemokine genes was observed after virulent Type I strain infection. In contrast, early innate response to the less virulent Type II strain was rapid, efficient and led to high levels of IL-8 and IL-6 secretion, whereas response to Type III parasites was intermediate. Early expression of b-defensin 2 gene was suppressed specifically by virulent Type I strain and its activation prior to infection in intestinal epithelial cells led to decreased parasite viability. These findings provide evidence for T. gondii strain virulence dependent down-modulation of early human intestinal epithelial cell innate responses and highlight the importance of these cells in host defense against this infection. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

This thesis investigates how air pollution, both natural and anthropogenic, affects changes in the proximal small intestine and ileum microbiota profile, as well as intestinal barrier integrity, histological changes, and inflammation. APO-E KO mice on a high fat diet were randomly selected to be exposed by whole body inhalation to either wood smoke (WS) or mixed vehicular exhaust (MVE), with filtered air (FA) acting as the control. Intestinal integrity and histology were assessed by observing expression of well- known structural components tight junction proteins (TJPs), matrix metallopeptidase-9 (MMP-9), and gel-forming mucin (MUC2), as well known inflammatory related factors: TNF-α, IL-1β, and toll-like receptor (TLR)-4. Bacterial profiling was done using DNA analysis of microbiota within the ileum, utilizing 16S metagenomics sequencing (Illumina miSeq) technique. Overall results of this experiment suggest that air pollution, both anthropogenic and natural, cause a breach in the intestinal barrier with an increase in inflammatory factors and a decrease in beneficial bacteria. This evidence suggests the possibility of air pollution being a potential causative agent of intestinal disease as well as a possible contributing mechanism for induction of systemic inflammation.