Gregory F. Sonnenberg, PhD
The immune system has numerous functions that are essential for human health, such as protection from infection or malignancy, regulation of metabolic homeostasis, and promotion of tissue repair. However, inappropriate immune responses drive chronic inflammatory disorders, such as inflammatory bowel disease, autoimmunity, neurodegeneration, allergies, or various cancers. Therefore, a greater understanding of the immune system will fundamentally advance biomedical research and drive the development of novel preventative, therapeutic and curative treatment strategies for human diseases. The only way to accomplish this is to fully define the complex cellular and molecular networks by which the immune system functionally interacts with itself, other mammalian cell types and beneficial or pathogenic microbes. This is the long-term research goal of the Sonnenberg Laboratory, with a focus on driving highly innovative advances, novel expertise, and paradigm-shifting research that requires out-of-the-box ideas and fresh perspectives.
The Sonnenberg Lab studies the pathways that regulate a state of health in the mammalian gastrointestinal tract. This is a considerable challenge as this organ system has an enormous surface area that is continuously exposed to dietary antigens, trillions of normally beneficial microbes (termed the microbiota), and frequent pathogens. Therefore, the intestinal immune system must be tolerant to innocuous stimuli, while providing protection from infections. This functional dichotomy could be why the intestine contains the largest and most sophisticated compartment of the mammalian immune system with numerous organized lymphoid structures and complex cellular networks. The Sonnenberg Laboratory has been at the forefront of interrogating novel pathways regulating immunity, inflammation, and tissue health in the mammalian intestine, with a particular focus on emerging families of innate lymphoid cells, dendritic cells, and distinct consortia of microbes.
The immune system at mucosal sites must be tightly regulated to mediate rapid immunity to invading pathogens, while limiting over-reactive responses that drive chronic inflammation. In particular, type 2 immune responses in the airway or gastrointestinal tract are essential to protect from helminth parasites, but if dysregulated, drive asthma and allergic inflammation. Despite this knowledge, we do not yet fully appreciate the complexity of cellular and molecular signals that control these responses, which will be critical for developing the next generation of preventative, therapeutic or curative treatments. The fundamental focus of this renewal application for the Mucosal Immunology Studies Team is to define novel pathways by which the type 2 immune response harnesses signals associated with the nervous system to regulate rapid mucosal immunity and inflammation. In this context, we will define: (i) the pathways that induce and regulate these neuronal signals, (ii) the functional significance of these pathways in type 2 mucosal immunity and inflammation, and (iii) whether it is possible to therapeutically target these signals to boost immunity to helminth infection or reduced chronic allergic inflammation. We will employ innovative approaches and develop new tools to address these fundamental gaps in knowledge, and where possible, translate our findings from mice into human samples. Results from these studies will significantly advance our understanding of the pathways that are essential to mediate rapid type 2 immunity and inflammation at mucosal sites and could provoke the next generation of preventative, therapeutic and curative treatment strategies.
Current Grant Support
Research in the Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936 and R01CA274534), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, the Meyer Cancer Center Collaborative Research Initiative, the Dalton Family Foundation, the Crohn's and Colitis Foundation, and the Cancer Research Institute.
Gregory F. Sonnenberg, PhD
Lyu M, Suzuki H, Kang L, Gaspal F, Zhou W, Goc J, Zhou L, Zhou J, Zhang W, JRI Live Cell Bank, Shen Z, Fox JG, Sockolow RE, Laufer TM, Fan Y, Eberl G, Withers DR, Sonnenberg GF. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature. 2022.
Zhou W, Zhou L, Zhou J; JRI Live Cell Bank, Chu C, Zhang C, Sockolow RE, Eberl G, Sonnenberg GF. ZBTB46 defines and regulates ILC3s that protect the intestine. Nature. 2022 Jul 13. doi: 10.1038/s41586-022-04934-4. Epub ahead of print. PMID: 35831503.
Zhou JZ, Sonnenberg GF. Coordination of Mucosal Immunity by Innate Lymphoid Cells. Adv Exp Med Biol. 2022;1365:113-134. doi: 10.1007/978-981-16-8387-9_8. PMID: 35567744.
Zhou L, Zhou W, Joseph AM, Chu C, Putzel GG, Fang B, Teng F, Lyu M, Yano H, Andreasson KI, Mekada E, Eberl G, Sonnenberg GF. Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nature Immunology. 2022 Jan 31. doi: 10.1038/s41590-021-01110-0. PMID: 35102343.
Grigg JB, Shanmugavadiv A, Regen T, Parkhurt CN, Ahmed A, Joseph AM, Mazzucco M, Gronke K, Diegenbach A, Eberl G, Vartanian T, Waisman A, Sonnenberg GF. Antigen presenting innate lymphoid cells orchestrate neuroinflammation. Nature. 2021 Dec;600(7890):707-712. doi: 10.1038/s41586-021-04136-4. Epub 2021 Dec 1. PMID: 34853467; PMCID: PMC8702489.
Teng F, Tachó-Piñot R, Sung B, Farber DL, Worgall S, Hammad H, Lambrecht BN, Hepworth MR, Sonnenberg GF. ILC3s control airway inflammation by limiting T cell responses to allergens and microbes. Cell Reports 2021 Nov 23;37(8):110051. doi: 10.1016/j.celrep.2021.110051. PMID: 34818549.
Goc J, Lv M, Bessman NJ, Flamar A, Sahota S, Suzuki H, Teng F, Putzel GG, JRI Live Cell Bank, Eberl G, Withers DR, Arthur JC, Shah MA, Sonnenberg GF. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer. Cell. 2021. Sep 16;184(19):5015-5030.e16. doi: 10.1016/j.cell.2021.07.029. PubMed PMID: 34407392
Bessman N.J., Mathieu J.R.R., Renassia C., Zhou L., Fung T.C., Fernandez K.C., Austin C., Moeller J.B., Zumerle S., Louis S., Vaulont S., Ajami N.J., Sokol H., Putzel G.G., Arvedson T., Sockolow R.E., Lakhal-Littleon S., Cloonan S.M., Arora M., Peyssonnaux C., Sonnenberg G.F. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science. 2020 Apr 10;368(6487):186-189. doi: 10.1126/science.aau6481. PubMed PMID: 32273468