ZFIN ID: ZDB-LAB-110615-1
Tobin Lab
PI/Director: Tobin, David
Contact Person: Tobin, David
Email: david.tobin@duke.edu
Address: Duke University Medical Center Box 3020 Jones Building, Rm. 218 Durham NC 27710 USA
Country: United States
Phone: 919.684.9152
Fax: (919) 684-2790
Line Designation: xt

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Tuberculosis: mycobacterial pathogenesis and host susceptibility

Tuberculosis kills ~1.5 million people annually. Our laboratory aims to understand the intricate interplay between mycobacteria and their hosts using a combination of model organism genetics, human genetics, pharmacology and high-resolution microscopy. By identifying key pathways utilized by the infecting bacteria and the host innate immune system, we hope to discover new therapeutic targets and interventions to combat this enduringly destructive disease.

Using a Mycobacterium/zebrafish model, we have performed a genetic screens to identify new host susceptibility loci. Zebrafish are natural hosts to Mycobacterium marinum, the closest relative of the Mycobacterium tuberculosis complex. Because zebrafish embryos and larvae are optically transparent, we are able to visualize the complex details of mycobacterial pathogenesis in whole, live animals. The facile genetics of the zebrafish allow us to map and positionally clone affected host susceptibility genes. In addition, zebrafish larvae are remarkably permeable to small molecules, providing a platform for whole-animal pharmacological manipulation of specific host immune responses.

Using these approaches, we have identified a novel immunoregulatory pathway that controls susceptibility to tuberculosis by modulating pro- and anti-inflammatory eicosanoids. Finally, we have shown that genes identified in the zebrafish model are also important in human tuberculosis. We find robust associations of human variants in this pathway with susceptibility to both tuberculosis and leprosy.


Wang, Y., Hsu, A.Y., Walton, E.M., Park, S.J., Syahirah, R., Wang, T., Zhou, W., Ding, C., Lemke, A.P., Zhang, G., Tobin, D.M., Deng, Q. (2021) A robust and flexible CRISPR/Cas9 based system for neutrophil-specific gene inactivation in zebrafish. Journal of Cell Science. 134(8):
Cronan, M.R., Hughes, E.J., Brewer, W.J., Viswanathan, G., Hunt, E.G., Singh, B., Mehra, S., Oehlers, S.H., Gregory, S.G., Kaushal, D., Tobin, D.M. (2021) A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization. Cell. 184(7):1757-1774.e14
McClean, C.M., Tobin, D.M. (2020) Early cell-autonomous accumulation of neutral lipids during infection promotes mycobacterial growth. PLoS One. 15:e0232251
Espenschied, S.T., Cronan, M.R., Matty, M.A., Mueller, O., Redinbo, M.R., Tobin, D.M., Rawls, J.F. (2019) Epithelial delamination is protective during pharmaceutical-induced enteropathy. Proceedings of the National Academy of Sciences of the United States of America. 116(34):16961-16970
Cronan, M.R., Tobin, D.M. (2019) Endogenous Tagging at the cdh1 Locus for Live Visualization of E-Cadherin Dynamics. Zebrafish. 16:324-325
Hortle, E., Johnson, K.E., Johansen, M.D., Nguyen, T., Shavit, J.A., Britton, W.J., Tobin, D.M., Oehlers, S.H. (2019) Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish. The Journal of infectious diseases. 220(3):524-534
Murdoch, C.C., Espenschied, S.T., Matty, M.A., Mueller, O., Tobin, D.M., Rawls, J.F. (2019) Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization. PLoS pathogens. 15:e1007381
Patton, E.E., Tobin, D.M. (2019) Spotlight on zebrafish: the next wave of translational research. Disease models & mechanisms. 12(3)
Matty, M.A., Knudsen, D.R., Walton, E.M., Beerman, R.W., Cronan, M.R., Pyle, C.J., Hernandez, R.E., Tobin, D.M. (2019) Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection. eLIFE. 8:
Cronan, M.R., Matty, M.A., Rosenberg, A.F., Blanc, L., Pyle, C.J., Espenschied, S.T., Rawls, J.F., Dartois, V., Tobin, D.M. (2018) An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nature Methods. 15:1098-1107
Walton, E.M., Cronan, M.R., Cambier, C.J., Rossi, A., Marass, M., Foglia, M.D., Brewer, W.J., Poss, K.D., Stainier, D.Y.R., Bertozzi, C.R., Tobin, D.M. (2018) Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling. Cell Host & Microbe. 24:514-525.e6
Alvarez, M.I., Glover, L.C., Luo, P., Wang, L., Theusch, E., Oehlers, S.H., Walton, E.M., Tram, T.T.B., Kuang, Y.L., Rotter, J.I., McClean, C.M., Chinh, N.T., Medina, M.W., Tobin, D.M., Dunstan, S.J., Ko, D.C. (2017) Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.. Proceedings of the National Academy of Sciences of the United States of America. 114(37):E7746-E7755
Oehlers, S.H., Cronan, M.R., Beerman, R.W., Johnson, M.G., Huang, J., Kontos, C.D., Stout, J.E., Tobin, D.M. (2017) Infection-induced vascular permeability aids mycobacterial growth. The Journal of infectious diseases. 215(5):813-817
Sullivan, C., Matty, M.A., Jurczyszak, D., Gabor, K.A., Millard, P.J., Tobin, D.M., Kim, C.H. (2017) Infectious disease models in zebrafish. Methods in cell biology. 138:101-136
Cronan, M.R., Beerman, R.W., Rosenberg, A.F., Saelens, J.W., Johnson, M.G., Oehlers, S.H., Sisk, D.M., Jurcic Smith, K.L., Medvitz, N.A., Miller, S.E., Trinh, L.A., Fraser, S.E., Madden, J.F., Turner, J., Stout, J.E., Lee, S., Tobin, D.M. (2016) Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection. Immunity. 45:861-876
Matty, M.A., Beerman, R.W., Tobin, D.M. (2016) Drug-Inducible, Cell-Specific Manipulation of Intracellular Calcium in Zebrafish through Mammalian TRPV1 Expression. Zebrafish. 13(4):374-5
Berg, R.D., Levitte, S., O'Sullivan, M.P., O'Leary, S.M., Cambier, C.J., Cameron, J., Takaki, K.K., Moens, C.B., Tobin, D.M., Keane, J., Ramakrishnan, L. (2016) Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration. Cell. 165:139-152
Matty, M.A., Oehlers, S.H., Tobin, D.M. (2016) Live Imaging of Host-Pathogen Interactions in Zebrafish Larvae. Methods in molecular biology (Clifton, N.J.). 1451:207-23
Beerman, R.W., Matty, M.A., Au, G.G., Looger, L.L., Choudhury, K.R., Keller, P.J., Tobin, D.M. (2015) Direct In Vivo Manipulation and Imaging of Calcium Transients in Neutrophils Identify a Critical Role for Leading-Edge Calcium Flux. Cell Reports. 13(10):2107-17
Cronan, M.R., Rosenberg, A.F., Oehlers, S.H., Saelens, J.W., Sisk, D.M., Smith, K.L., Lee, S., Tobin, D.M. (2015) CLARITY and PACT-based imaging of adult zebrafish and mouse for whole-animal analysis of infections. Disease models & mechanisms. 8(12):1643-50
Walton, E.M., Cronan, M.R., Beerman, R.W., Tobin, D.M. (2015) The Macrophage-Specific Promoter mfap4 Allows Live, Long-Term Analysis of Macrophage Behavior during Mycobacterial Infection in Zebrafish. PLoS One. 10:e0138949
Tenor, J.L., Oehlers, S.H., Yang, J.L., Tobin, D.M., Perfect, J.R. (2015) Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion. mBio. 6(5):e01425-15
Wang, L., Oehlers, S.H., Espenschied, S.T., Rawls, J.F., Tobin, D.M., Ko, D.C. (2015) CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation. Genome biology. 16:190
Marjoram, L., Alvers, A., Deerhake, M.E., Bagwell, J., Mankiewicz, J., Cocchiaro, J.L., Beerman, R.W., Willer, J., Sumigray, K.D., Katsanis, N., Tobin, D.M., Rawls, J.F., Goll, M.G., Bagnat, M. (2015) Epigenetic control of intestinal barrier function and inflammation in zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 112(9):2770-5
Oehlers, S.H., Cronan, M.R., Scott, N.R., Thomas, M.I., Okuda, K.S., Walton, E.M., Beerman, R.W., Crosier, P.S., Tobin, D.M. (2015) Interception of host angiogenic signalling limits mycobacterial growth. Nature. 517(7536):612-5
Cronan, M.R., Tobin, D.M. (2014) Fit for consumption: zebrafish as a model for tuberculosis. Disease models & mechanisms. 7:777-784
Whipps, C.M., Moss, L.G., Sisk, D.M., Murray, K.N., Tobin, D.M., and Moss, J.B. (2014) Detection of autofluorescent Mycobacterium chelonae in living zebrafish. Zebrafish. 11(1):76-82
Cambier, C.J., Takaki, K.K., Larson, R.P., Hernandez, R.E., Tobin, D.M., Urdahl, K.B., Cosma, C.L., and Ramakrishnan, L. (2014) Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature. 505(7482):218-222
Tobin, D.M., and Ramakrishnan, L. (2013) TB: the Yin and Yang of lipid mediators. Current opinion in pharmacology. 13(4):641-5
Tobin, D.M., Roca, F.J., Oh, S.F., McFarland, R., Vickery, T.W., Ray, J.P., Ko, D.C., Zou, Y., Bang, N.D., Chau, T.T., Vary, J.C., Hawn, T.R., Dunstan, S.J., Farrar, J.J., Thwaites, G.E., King, M.C., Serhan, C.N., and Ramakrishnan, L. (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 148(3):434-446
Tobin, D.M., May, R.C., and Wheeler, R.T. (2012) Zebrafish: a see-through host and a fluorescent toolbox to probe host-pathogen interaction. PLoS pathogens. 8(1):e1002349
Tobin, D.M., Vary, J.C. Jr, Ray, J.P., Walsh, G.S., Dunstan, S.J., Bang, N.D., Hagge, D.A., Khadge, S., King, M.C., Hawn, T.R., Moens, C.B., and Ramakrishnan, L. (2010) The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans. Cell. 140(5):717-730
Tobin, D.M., and Ramakrishnan, L. (2008) Comparative pathogenesis of Mycobacterium marinum and Mycobacterium tuberculosis. Cellular Microbiology. 10(5):1027-1039