Enteric bacterial infections remain one of the greatest public health challenges worldwide. An estimated four to six million deaths per year worldwide are caused by bacterial-induced diarrhea and the associated dehydration represents the second most common cause of infant mortality around the world. Enteric bacterial infections and diarrhea are also an important public health concern for travelers and US Forces overseas. The goals of this proposal are to interrogate the influence of innate lymphoid cells (ILCs) in the regulation of innate and adaptive immunity following enteric bacterial infection. Employing Citrobacter rodentium, an experimental model of human enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC or EHEC) infection, our preliminary studies identified a role for IL-23-dependent IL-22 in innate immunity to infection. The dominant cellular source of IL-23-dependent IL-22 in Citrobacter-infected mice was a population of ROR3t-positive ILCs that expressed c-kit and CD90, and in vivo depletion of ILCs in Citrobacter-infected Rag-/- mice was associated with a defect in protective innate immunity to infection. ILCs expressed the thymic stromal lymphopoietin receptor (TSLPR) and deletion of TSLPR resulted in exaggerated ILC responses and enhanced immunity to Citrobacter, indicating that TSLP inhibits ILC-dependent innate immunity in vivo. In addition, a sub-population of ILCs expressed MHC class II and costimulatory molecules and could promote T cell proliferation in vitro, suggesting that these cells also have the capacity to promote T cell-dependent immunity in vivo. Employing selective in vivo depletions, adoptive transfers and cell lineage-specific deletion strategies, three specific aims of this project will determine (i) what signals promote ILC responses in vivo and what is their role in innate immunity to Citrobacter, (ii) how TSLP-TSLPR interactions inhibit ILC responses and innate immunity, and (iii) how ILC-intrinsic MHC class II expression influences CD4pos T cell responses and immunity to Citrobacter. The results of these studies will provide a framework to test the therapeutic potential of manipulating ILC responses in the promotion of anti-bacterial immunity and the treatment of intestinal inflammation. We anticipate that defining the contribution of ILCs to anti-bacterial immunity will direct future clinical efforts to boost innate immunity in the context of human conditions involving immunodeficiency including HIV, cancer and transplantation, to improve the efficacy of oral vaccines, and to dampen ILC responses and reduce chronic inflammation in diseases such as inflammatory bowel disease.
Enteric bacterial infections remain one of the greatest public health challenges worldwide. An estimated four to six million deaths per year worldwide are caused by bacterial-induced diarrhea and the associated dehydration represents the second most common cause of infant mortality around the world. Enteric bacterial infections and diarrhea are also an important public health concern for travelers and US Forces overseas. The goals of this proposal are to understand the role of a population of immune cells called innate lymphoid cells in the development of anti-bacterial immune responses and apply this knowledge in the design of successful new anti-bacterial drugs and vaccines.
| Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061 |
| Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466 |
| Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20 |
| Chu, Coco; Moriyama, Saya; Li, Zhi et al. (2018) Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183. Cell Rep 23:3750-3758 |
| Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B et al. (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282-286 |
| Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860 |
| Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356 |
| Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65 |
| Alex, Aneesh; Tait Wojno, Elia D; Artis, David et al. (2016) Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. Methods Mol Biol 1422:127-36 |
| Rak, Gregory D; Osborne, Lisa C; Siracusa, Mark C et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496 |
Showing the most recent 10 out of 62 publications
