Grant: Discovery Grants Program - Individual

Commensal microbes live inside the host in symbiosis. Probiotics are live commensals that have been used for centuries to replenish normal or beneficial gut and urogenital microflora. Long-term objectives of my research program are to understand how the host maintains immunological symbiosis with commensals and what immunological effects probiotics have on the host. During the last 5 years of NSERC support, our research program has focused on unraveling the mechanisms of the host cells in sensing bacterial probiotics and their effects on the host immune responses. We have demonstrated that the probiotic strain of Lactobacillus rhamnosus GR1 (GR1) and its secreted products have immunomodulatory effects on macrophages, dendritic cells, intestinal lamina propria cells and placental trophoblasts. GR1 as well as other strains of Lactobacillus rhamnosus preferentially and potently produce the immunomodulatory cytokine granulocyte colony-stimulating factor (G-CSF) in these cells, which may play important roles in maintaining immunological homeostasis of intestine and placenta. This research proposal is to further study the cellular and signaling mechanisms by which GR1, GR1-secreted factor(s) and G-CSF in modulating macrophage differentiation, activation and survival. The followings are specific aims of the study:Aim 1: Identify/purify the GR1-factor(s), and examine its/their signaling and epigenetic mechanisms responsible for preferential production of G-CSF in macrophages. Aim 2. Examining the role and mechanisms of G-CSF in macrophage differentiation and survival in bone marrow cells, THP-1 cells and the intestine. The proposed study will provide detailed information on how lactobacilli modulate macrophage activation and how G-CSF highly produced by lactobacillus-exposed macrophages affects myeloid cell differentiation and cell survival. Overall, these studies will unravel how commensals and probiotics modulate the host immune system and maintain symbiosis in the host.