Massachusetts General Hospital
Center for Computational & Integrative Biology
185 Cambridge Street - Simches 7222
Boston, MA 02114
The overall goal in the laboratory is to discover and understand the function of important mediators and effectors involved in innate (autophagy, pathogen-containing vacuole) and adaptive (T cell activation) immunity. Especially of interest are the cellular components and regulatory networks which interact dynamically within temporal, spatial, and pathophysiological contexts of innate immunity. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays (RNAi and cDNA screens) and computational methods. Using these approaches we are interested in addressing the following issues: 1) the mechanisms by which autophagy regulates innate and adaptive immunity, 2) the roles of NOD/LRR domains in sensing microbial effectors, and 3) how innate immune pathways are dysregulated in mucosal immunity. The adaptive immunity program focuses on elucidating signal transduction pathways coordinated by the CARMA/Dlg family of scaffold proteins.
Crohn’s disease and ulcerative colitis are debilitating inflammatory diseases of the gastrointestinal tract collectively known as inflammatory bowel diseases. Among complex diseases, genetics has been particularly successful in the identification of genes for IBD, with recent efforts in genome-wide association studies bringing the total number of loci to >100. These studies have highlighted the significance of the relationship between intracellular responses to microbes and the regulation of adaptive immunity in the pathogenesis of IBD. With rapid progress in human genetics it has become clear that a major challenge in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. The lab focuses on applying novel genomic, genetic, and chemical biology approaches to gain insights into the function of genetic variants underlying common inflammatory disease and to explore the potential for reversing the effects of susceptibility alleles. We are also investigating relationships between IBD and the gut microbiome, including interactions between host genetics and gut microbiota.
Conway KL, Kuballa P, Song JH, Patel KK, Castoreno AB, Yilmaz OH, Jijon HB, Zhang M, Aldrich LN, Villablanca EJ, Peloquin JM, Goel G, Lee IA, Mizoguchi E, Shi HN, Bhan AK, Shaw SY, Schreiber SL, Virgin HW, Shamji AF, Stappenbeck TS, Reinecker HC, Xavier RJ. Atg16l1 is Required for Autophagy in Intestinal Epithelial Cells and Protection of Mice from Salmonella Infection. Gastroenterology. 2013. PMID: 23973919.
Graham DB, Xavier RJ. From genetics of inflammatory bowel disease towards mechanistic insights. Trends Immunol. 2013;34(8):371-8. PMID: 23639549.
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O'Neill LA. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496(7444):238-42. PMID: 23535595.
Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM, Goldberg MB, Xavier RJ. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe. 2012;12(6):778-90. PMID: 23245322.
Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, Arts P, Verwiel ET, Gresnigt MS, Fransen K, van Sommeren S, Oosting M, Cheng SC, Joosten LA, Hoischen A, Kullberg BJ, Scott WK, Perfect JR, van der Meer JW, Wijmenga C, Netea MG, Xavier RJ. Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun. 2013;4:1342. PMID: 23299892.
For a complete listing of publications click here.
Last Update: 1/6/2014