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Breaking Down the Barrier: Novel Insights Into the Role of Intestinal Microvilli, M cells, and Exploiting "Innate" B Cells as Therapeutic Targets

  • Author(s): Bennett, Kaila Marie
  • Advisor(s): Lo, David D
  • et al.
Abstract

The mucosal barrier is a well-armed opponent against the microbial world that works to limit entry of pathogenic bacteria, while maintaining a level of tolerance towards the resident microbiota. This paradoxical function is carried out by three distinct barriers i.e. physical, innate, and adaptive. Microvilli, a component of the physical barrier, while noted for their capacity to take up nutrients, have been overlooked as playing a role in the prevention of bacterial entry. We report that microvilli generate an electrostatic barrier that directs pathogen binding based on their zeta potential (proxy of surface charge). By knocking out microvilli in an intestinal cell line we were able to probe how bacterial adherence/uptake was affected by the absence of microvilli. This electrostatic barrier may have important functional consequences at the surface of the follicle- associate epithelium (e.g. Peyer's patch), where interdispersed between adjacent enterocytes reside M cells, which lack microvilli. M cells are a feature of the adaptive barrier, and are known for their ability to transcytose luminal antigens in the small intestine. However, their role in the large intestine has been neglected. We describe the induction of M cells in the colonic epithelium during intestinal inflammation, which seems to be reliant on the pro-inflammatory cytokine TNFα, as treatment with anti-TNFα largely blocked M cell induction. This was confirmed using a novel reporter mouse that was engineered to express DsRed in both neutrophils and M cells. Thus, M cells may play a greater role during inflammation. Furthermore, M cells also mediate adaptive immune response through associated B lymphocytes. The follicle of the Peyer's patch is heavily populated with B lymphocytes that help to generate secretory IgA. Large portions of these B cells are of the B1 subset, known for their capacity to stimulate T cell independent antibody response in the presences of polymeric antigens. We describe the design of a T cell independent antigen using polymeric flagellin as a vaccine backbone to stimulate the T cell independent B cells. We incorporated the envelope protein from dengue virus 2 into the D3 domain of flagellin and these hybrid filaments were able to produce a humoral response in both T cell dependent and independent models.

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