Xavier Laboratory

Overview

The primary research goal of the Xavier Laboratory at Massachusetts General Hospital is to discover and understand the function of important mediators and effectors involved in both the innate and adaptive immune systems. Of particular interest are the cellular components and regulatory networks that 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 and computational methods.

Research Projects

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. Of particular interest are the cellular components and regulatory networks, which interact dynamically within temporal, spatial and patho-physiological 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 questions:

1. What are the mechanisms by which autophagy regulates innate and adaptive immunity?
2. What are the roles of NOD/LRR domains in sensing microbial effectors?
3. How are innate immune pathways dysregulated in mucosal immunity?

The adaptive immunity program focuses on the elucidation of 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 genes to more than 40. 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 the 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 influences on the biology of health and disease. Our lab focuses on applying novel genomic, genetic, and chemical biology approaches to gain insights into the function of genetic variants underlying common inflammatory diseases and to explore the potential for reversing the effects of susceptibility alleles.

Systems biology approaches to understand human disease signaling networks

The discovery of important mediators and effectors involved in immunity requires a deeper exploration of how these function as integrated systems. Especially of interest are the cellular components and regulatory networks which interact dynamically within temporal, spatial and pathophysiological contexts. We are pursuing integrative systems approaches that closely couple genome-wide experimentation with bioinformatics and computational methods.

We hope to gain additional insights about the immune system in terms of the underlying interaction and regulatory networks that define functional modules at the host-pathogen interface. In addition the team of computational biologists and mathematicians in the group are developing testable models using information from genome-wide studies and high-throughput screens to gain insight into molecular mechanisms of autoimmune disorders.

Publications

1. Avraham R, Haseley N, Brown D, Penaranda C, Jijon HB, Trombetta JJ, Satija R, Shalek AK, Xavier RJ, Regev A, Hung DT. Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses. Cell. 2015;162(6):1309-21. PMID: 26343579.
2. Korem T, Zeevi D, Suez J, Weinberger A, Avnit-Sagi T, Pompan-Lotan M, Matot E, Jona G, Harmelin A, Cohen N, Sirota-Madi A, Thaiss CA, Pevsner-Fischer M, Sorek R, Xavier RJ, Elinav E, Segal E. Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science. 2015;349(6252):1101-6. PMID: 26229116.
3. Baxt LA, Xavier RJ. Role of Autophagy in the Maintenance of Intestinal Homeostasis. Gastroenterology. 2015;149(3):553-62. PMID: 26170139.
4. Cao Z, Conway KL, Heath RJ, Rush JS, Leshchiner ES, Ramirez-Ortiz ZG, Nedelsky NB, Huang H, Ng A, Gardet A, Cheng SC, Shamji AF, Rioux JD, Wijmenga C, Netea MG, Means TK, Daly MJ, Xavier RJ. Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. Immunity. 2015;43(4):715-26. PMID: 26488816.
5. Fu J, Bonder MJ, Cenit MC, Tigchelaar EF, Maatman A, Dekens JA, Brandsma E, Marczynska J, Imhann F, Weersma RK, Franke L, Poon TW, Xavier RJ, Gevers D, Hofker MH, Wijmenga C, Zhernakova A. The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids. Circ Res. 2015;117(9):817-24. PMID: 26358192.
6. Pringle PL, Stewart KO, Peloquin JM, Sturgeon HC, Nguyen D, Sauk J, Garber JJ, Yajnik V, Ananthakrishnan AN, Chan AT, Xavier RJ, Khalili H. Body Mass Index, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease. Inflamm Bowel Dis. 2015;21(10):2304-10. PMID: 26181430.
7. Luo C, Knight R, Siljander H, Knip M, Xavier RJ, Gevers D. ConStrains identifies microbial strains in metagenomic datasets. Nat Biotechnol. 2015;33(10):1045-52. PMID: 26344404.
8. Desch AN, Gibbings SL, Goyal R, Kolde R, Bednarek J, Bruno T, Slansky JE, Jacobelli J, Mason R, Ito Y, Messier E, Randolph GJ, Prabagar M, Atif SM, Segura E, Xavier RJ, Bratton DL, Janssen WJ, Henson PM, Jakubzick CV. Flow Cytometric Analysis of Mononuclear Phagocytes in Non-diseased Human Lung and Lung-draining Lymph Nodes. Am J Respir Crit Care Med. 2015. PMID: 26551758.
9. Ananthakrishnan AN, Cagan A, Cai T, Gainer VS, Shaw SY, Churchill S, Karlson EW, Murphy SN, Kohane I, Liao KP, Xavier RJ. Common Genetic Variants Influence Circulating Vitamin D Levels in Inflammatory Bowel Diseases. Inflamm Bowel Dis. 2015;21(11):2507-14. PMID: 26241000.
10. Wlodarska M, Kostic AD, Xavier RJ. An integrative view of microbiome-host interactions in inflammatory bowel diseases. Cell Host Microbe. 2015;17(5):577-91. PMID: 25974300.
11. Jaeger M, van der Lee R, Cheng SC, Johnson MD, Kumar V, Ng A, Plantinga TS, Smeekens SP, Oosting M, Wang X, Barchet W, Fitzgerald K, Joosten LA, Perfect JR, Wijmenga C, van de Veerdonk FL, Huynen MA, Xavier RJ, Kullberg BJ, Netea MG. The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections. Eur J Clin Microbiol Infect Dis. 2015;34(5):963-74. PMID: 25579795.
12. Haberman Y, Tickle TL, Dexheimer PJ, Kim MO, Tang D, Karns R, Baldassano RN, Noe JD, Rosh J, Markowitz J, Heyman MB, Griffiths AM, Crandall WV, Mack DR, Baker SS, Huttenhower C, Keljo DJ, Hyams JS, Kugathasan S, Walters TD, Aronow B, Xavier RJ, Gevers D, Denson LA. Corrigendum. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J Clin Invest. 2015;125(3):1363. PMID: 25729854.
13. Sarmento OF, Svingen PA, Xiong Y, Xavier RJ, McGovern D, Smyrk TC, Papadakis KA, Urrutia RA, Faubion WA. A novel role for KLF14 in T regulatory cell differentiation. Cell Mol Gastroenterol Hepatol. 2015;1(2):188-202 e4. PMID: 25750932.
14. Begun J, Lassen KG, Jijon HB, Baxt LA, Goel G, Heath RJ, Ng A, Tam JM, Kuo SY, Villablanca EJ, Fagbami L, Oosting M, Kumar V, Schenone M, Carr SA, Joosten LA, Vyas JM, Daly MJ, Netea MG, Brown GD, Wijmenga C, Xavier RJ. Integrated Genomics of Crohn's Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy. Cell Rep. 2015;11(12):1905-18. PMID: 26095365.
15. Quevrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, Miquel S, Carlier L, Bermudez-Humaran LG, Pigneur B, Lequin O, Kharrat P, Thomas G, Rainteau D, Aubry C, Breyner N, Afonso C, Lavielle S, Grill JP, Chassaing G, Chatel JM, Trugnan G, Xavier R, Langella P, Sokol H, Seksik P. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut. 2015. PMID: 26045134.
16. Causton B, Ramadas RA, Cho JL, Jones K, Pardo-Saganta A, Rajagopal J, Xavier RJ, Medoff BD. CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation. J Immunol. 2015;195(2):683-94. PMID: 26041536.
17. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL, Zhao G, Fleshner P, Stappenbeck TS, McGovern DP, Keshavarzian A, Mutlu EA, Sauk J, Gevers D, Xavier RJ, Wang D, Parkes M, Virgin HW. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 2015;160(3):447-60. PMID: 25619688.
18. Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang JK, Israelsen WJ, Keane J, Thomas C, Clish C, Vander Heiden M, Xavier RJ, O'Neill LA. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65-80. PMID: 25565206.
19. Qian F, Goel G, Meng H, Wang X, You F, Devine L, Raddassi K, Garcia MN, Murray KO, Bolen CR, Gaujoux R, Shen-Orr SS, Hafler D, Fikrig E, Xavier R, Kleinstein SH, Montgomery RR. Systems immunology reveals markers of susceptibility to West Nile virus infection. Clin Vaccine Immunol. 2015;22(1):6-16. PMID: 25355795.
20. Paulus GL, Xavier RJ. Autophagy and checkpoints for intracellular pathogen defense. Curr Opin Gastroenterol. 2015;31(1):14-23. PMID: 25394238.
21. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyotylainen T, Hamalainen AM, Peet A, Tillmann V, Poho P, Mattila I, Lahdesmaki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen H, Ilonen J, Virtanen SM, Clish CB, Oresic M, Huttenhower C, Knip M, Group DS, Xavier RJ. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe. 2015;17(2):260-73. PMID: 25662751.
22. Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, International Inflammatory Bowel Disease Genetics C, Australia, New Zealand I, Belgium IBDGC, Italian Group for IBDGC, Consortium NIBDG, United Kingdom I, Wellcome Trust Case Control C, Quebec IBDGC, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015;47(2):172-9. PMID: 25559196.
23. Kuo SY, Castoreno AB, Aldrich LN, Lassen KG, Goel G, Dancik V, Kuballa P, Latorre I, Conway KL, Sarkar S, Maetzel D, Jaenisch R, Clemons PA, Schreiber SL, Shamji AF, Xavier RJ. Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Proc Natl Acad Sci U S A. 2015;112(31):E4281-7. PMID: 26195741.
24. Aldrich LN, Kuo SY, Castoreno AB, Goel G, Kuballa P, Rees MG, Seashore-Ludlow BA, Cheah JH, Latorre IJ, Schreiber SL, Shamji AF, Xavier RJ. Discovery of a Small-Molecule Probe for V-ATPase Function. J Am Chem Soc. 2015;137(16):5563-8. PMID: 25860544.
25. Selleck EM, Orchard RC, Lassen KG, Beatty WL, Xavier RJ, Levine B, Virgin HW, Sibley LD. A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-gamma-Activated Human Cells. MBio. 2015;6(5):e01157-15. PMID: 26350966.
26. Morgan XC, Kabakchiev B, Waldron L, Tyler AD, Tickle TL, Milgrom R, Stempak JM, Gevers D, Xavier RJ, Silverberg MS, Huttenhower C. Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease. Genome Biol. 2015;16:67. PMID: 25887922.
27. Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife. 2015;4. PMID: 25998054.
28. Graham DB, Becker CE, Doan A, Goel G, Villablanca EJ, Knights D, Mok A, Ng AC, Doench JG, Root DE, Clish CB, Xavier RJ. Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst. Nat Commun. 2015;6:7838. PMID: 26194095.
29. Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, Cheng SC, Ratter J, Berentsen K, van der Ent MA, Sharifi N, Janssen-Megens EM, Ter Huurne M, Mandoli A, van Schaik T, Ng A, Burden F, Downes K, Frontini M, Kumar V, Giamarellos-Bourboulis EJ, Ouwehand WH, van der Meer JW, Joosten LA, Wijmenga C, Martens JH, Xavier RJ, Logie C, Netea MG, Stunnenberg HG. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086. PMID: 25258085.
30. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, Deen PM, Logie C, O'Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345(6204):1250684. PMID: 25258083.
31. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, Dahlman JE, Parnas O, Eisenhaure TM, Jovanovic M, Graham DB, Jhunjhunwala S, Heidenreich M, Xavier RJ, Langer R, Anderson DG, Hacohen N, Regev A, Feng G, Sharp PA, Zhang F. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell. 2014;159(2):440-55. PMID: 25263330.
32. Lassen KG, Xavier RJ. An alteration in ATG16L1 stability in Crohn disease. Autophagy. 2014;10(10):1858-60. PMID: 25136803.
33. Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 2014;10(10):e1004485. PMID: 25356988.
34. Lassen KG, Kuballa P, Conway KL, Patel KK, Becker CE, Peloquin JM, Villablanca EJ, Norman JM, Liu TC, Heath RJ, Becker ML, Fagbami L, Horn H, Mercer J, Yilmaz OH, Jaffe JD, Shamji AF, Bhan AK, Carr SA, Daly MJ, Virgin HW, Schreiber SL, Stappenbeck TS, Xavier RJ. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci U S A. 2014;111(21):7741-6. PMID: 24821797.
35. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146(6):1489-99. PMID: 24560869.
36. Ananthakrishnan AN, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases. Inflamm Bowel Dis. 2014;20(5):783-9. PMID: 24651583.
37. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, Schwager E, Knights D, Song SJ, Yassour M, Morgan XC, Kostic AD, Luo C, Gonzalez A, McDonald D, Haberman Y, Walters T, Baker S, Rosh J, Stephens M, Heyman M, Markowitz J, Baldassano R, Griffiths A, Sylvester F, Mack D, Kim S, Crandall W, Hyams J, Huttenhower C, Knight R, Xavier RJ. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe. 2014;15(3):382-92. PMID: 24629344.
38. de Luca A, Smeekens SP, Casagrande A, Iannitti R, Conway KL, Gresnigt MS, Begun J, Plantinga TS, Joosten LA, van der Meer JW, Chamilos G, Netea MG, Xavier RJ, Dinarello CA, Romani L, van de Veerdonk FL. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A. 2014;111(9):3526-31. PMID: 24550444.
39. Ananthakrishnan AN, Huang H, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort. Am J Gastroenterol. 2014;109(3):395-400. PMID: 24419484.
40. Huttenhower C, Kostic AD, Xavier RJ. Inflammatory bowel disease as a model for translating the microbiome. Immunity. 2014;40(6):843-54. PMID: 24950204.
41. Dunne JL, Triplett EW, Gevers D, Xavier R, Insel R, Danska J, Atkinson MA. The intestinal microbiome in type 1 diabetes. Clin Exp Immunol. 2014;177(1):30-7. PMID: 24628412.
42. VanDussen KL, Liu TC, Li D, Towfic F, Modiano N, Winter R, Haritunians T, Taylor KD, Dhall D, Targan SR, Xavier RJ, McGovern DP, Stappenbeck TS. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease. Gastroenterology. 2014;146(1):200-9. PMID: 24076061.
43. Canny SP, Goel G, Reese TA, Zhang X, Xavier R, Virgin HW. Latent gammaherpesvirus 68 infection induces distinct transcriptional changes in different organs. J Virol. 2014;88(1):730-8. PMID: 24155394.
44. Pulloor NK, Nair S, Kostic AD, Bist P, Weaver JD, Riley AM, Tyagi R, Uchil PD, York JD, Snyder SH, Garcia-Sastre A, Potter BV, Lin R, Shears SB, Xavier RJ, Krishnan MN. Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog. 2014;10(2):e1003981. PMID: 24586175.
45. Guo AY, Stevens BW, Wilson RG, Russell CN, Cohen MA, Sturgeon HC, Thornton A, Giallourakis C, Khalili H, Nguyen DD, Sauk J, Yajnik V, Xavier RJ, Ananthakrishnan AN. Early life environment and natural history of inflammatory bowel diseases. BMC Gastroenterol. 2014;14(1):216. PMID: 25510175.
46. Tam JM, Mansour MK, Khan NS, Seward M, Puranam S, Tanne A, Sokolovska A, Becker CE, Acharya M, Baird MA, Choi AM, Davidson MW, Segal BH, Lacy-Hulbert A, Stuart LM, Xavier RJ, Vyas JM. Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages. J Infect Dis. 2014;210(11):1844-54. PMID: 24842831.
47. Draberova L, Bugajev V, Potuckova L, Halova I, Bambouskova M, Polakovicova I, Xavier RJ, Seed B, Draber P. Transmembrane adaptor protein PAG/CBP is involved in both positive and negative regulation of mast cell signaling. Mol Cell Biol. 2014;34(23):4285-300. PMID: 25246632.
48. Doench JG, Hartenian E, Graham DB, Tothova Z, Hegde M, Smith I, Sullender M, Ebert BL, Xavier RJ, Root DE. Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation. Nat Biotechnol. 2014;32(12):1262-7. PMID: 25184501.
49. Sundberg TB, Xavier RJ, Schreiber SL, Shamji AF. Small-molecule control of cytokine function: new opportunities for treating immune disorders. Curr Opin Chem Biol. 2014;23:23-30. PMID: 25222143.
50. Kumar V, Wijmenga C, Xavier RJ. Genetics of immune-mediated disorders: from genome-wide association to molecular mechanism. Curr Opin Immunol. 2014;31:51-7. PMID: 25458995.