Cronan, Mark R., Erika J. Hughes, W Jared Brewer, Gopinath Viswanathan, Emily G. Hunt, Bindu Singh, Smriti Mehra, et al. “A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization.” Cell 184, no. 7 (April 1, 2021): 1757-1774.e14. https://doi.org/10.1016/j.cell.2021.02.046.
David M. Tobin, PhD
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 identified new host susceptibility loci for tuberculosis. 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.
We have identified novel pathways that modulate susceptibility to tuberculosis. We have shown that genes identified in the zebrafish model are also important in human tuberculosis. We find robust associations of human variants in a specific eicosanoid pathway with susceptibility to both tuberculosis and leprosy.
We have active collaborations in both Vietnam and Guatemala. In Guatemala, we are working with the Clínica Familiar Luis Angel García and the Asociación de Salud Integral to support projects involving HIV-infected patients and to understand the dynamics of TB transmission in Central America.
Education and Training
- Ph.D., University of California San Francisco, School of Medicine, 2002
Selected Grants and Awards
- Combined Use of Statistical Process Control and Whole Genome Sequencing to Detect and Investigate Nontuberculous Mycobacterial Clusters and Outbreaks (K08)
- Cell and Molecular Biology Training Program
- Interdisciplinary Research Training Program in AIDS
- Genetic and Genomics Training Grant
- Basic Immunology Training Program
- Molecular Mycology and Pathogenesis Training Program
- Genetic Dissection of Cell-Specific Roles in Mycobacterial Granuloma Architecture
- Duke CTSA (TL1)
- Cellular Mechanisms of Angiogenesis in Response to Mycobacterial Infection
- The Genetic Basis of Bone Disease in Mycobacterial Infection
- The Genetic Basis of Virulence in Cryptococcus Neoformans
- Medical Scientist Training Program
- Innate Immune Determinants of Granuloma Formation in the Zebrafish
- Genetic Dissection of Angiogenesis in the Tuberculous Granuloma
- Genetics Training Grant
- Organization and Function of Cellular Structure
- Role of Cholesterol Efflux Blockade in Mycobacterial Infection In Vivo
- Functional Characterization of the GNAQ somatic mutation causing Sturge Weber syndrome
- The Genetic Basis of Bone Disease in Mycobacterial Infection
- The Genetic Architecture of Virulence in Cryptococcus Neoformans
- Lightsheet Imaging System
- Role of Developmental Signaling Pathways in Tuberculosis Pathogenesis
- Modulating Eicosanoids to Treat Tuberculosis: Personalized, Host-directed Therapy
Matty, Molly A., Daphne R. Knudsen, Eric M. Walton, Rebecca W. Beerman, Mark R. Cronan, Charlie J. Pyle, Rafael E. Hernandez, and David M. Tobin. “Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection.” Elife 8 (January 29, 2019). https://doi.org/10.7554/eLife.39123.
Cronan, Mark R., Molly A. Matty, Allison F. Rosenberg, Landry Blanc, Charlie J. Pyle, Scott T. Espenschied, John F. Rawls, Véronique Dartois, and David M. Tobin. “An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas.” Nat Methods 15, no. 12 (December 2018): 1098–1107. https://doi.org/10.1038/s41592-018-0215-8.
Walton, Eric M., Mark R. Cronan, C. J. Cambier, Andrea Rossi, Michele Marass, Matthew D. Foglia, W Jared Brewer, et al. “Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling.” Cell Host Microbe 24, no. 4 (October 10, 2018): 514-525.e6. https://doi.org/10.1016/j.chom.2018.09.004.
Jain, Sanjay K., David M. Tobin, Elizabeth W. Tucker, Vishwanath Venketaraman, Alvaro A. Ordonez, Lakshmi Jayashankar, Omar K. Siddiqi, et al. “Tuberculous meningitis: a roadmap for advancing basic and translational research.” Nat Immunol 19, no. 6 (June 2018): 521–25. https://doi.org/10.1038/s41590-018-0119-x.
Cronan, Mark R., Rebecca W. Beerman, Allison F. Rosenberg, Joseph W. Saelens, Matthew G. Johnson, Stefan H. Oehlers, Dana M. Sisk, et al. “Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection.” Immunity 45, no. 4 (October 18, 2016): 861–76. https://doi.org/10.1016/j.immuni.2016.09.014.
Berg, Russell D., Steven Levitte, Mary P. O’Sullivan, Seónadh M. O’Leary, C. J. Cambier, James Cameron, Kevin K. Takaki, et al. “Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.” Cell 165, no. 1 (March 24, 2016): 139–52. https://doi.org/10.1016/j.cell.2016.02.034.
Beerman, Rebecca W., Molly A. Matty, Gina G. Au, Loren L. Looger, Kingshuk Roy Choudhury, Philipp J. Keller, and David M. Tobin. “Direct In Vivo Manipulation and Imaging of Calcium Transients in Neutrophils Identify a Critical Role for Leading-Edge Calcium Flux.” Cell Rep 13, no. 10 (December 15, 2015): 2107–17. https://doi.org/10.1016/j.celrep.2015.11.010.
Cronan, Mark R., Allison F. Rosenberg, Stefan H. Oehlers, Joseph W. Saelens, Dana M. Sisk, Kristen L. Jurcic Smith, Sunhee Lee, and David M. Tobin. “CLARITY and PACT-based imaging of adult zebrafish and mouse for whole-animal analysis of infections.” Dis Model Mech 8, no. 12 (December 2015): 1643–50. https://doi.org/10.1242/dmm.021394.
Saelens, Joseph W., Dalia Lau-Bonilla, Anneliese Moller, Narda Medina, Brenda Guzmán, Maylena Calderón, Raúl Herrera, et al. “Whole genome sequencing identifies circulating Beijing-lineage Mycobacterium tuberculosis strains in Guatemala and an associated urban outbreak.” Tuberculosis (Edinburgh, Scotland) 95, no. 6 (December 2015): 810–16. https://doi.org/10.1016/j.tube.2015.09.001.
Tenor, Jennifer L., Stefan H. Oehlers, Jialu L. Yang, David M. Tobin, and John R. Perfect. “Live Imaging of Host-Parasite Interactions in a Zebrafish Infection Model Reveals Cryptococcal Determinants of Virulence and Central Nervous System Invasion.” Mbio 6, no. 5 (September 29, 2015): e01425–e01415. https://doi.org/10.1128/mBio.01425-15.
Oehlers, S. H., M. R. Cronan, N. R. Scott, M. I. Thomas, K. S. Okuda, E. M. Walton, R. W. Beerman, P. S. Crosier, and D. M. Tobin. “Interception of host angiogenic signalling limits mycobacterial growth.” Nature 517, no. 7536 (January 29, 2015): 612–15. https://doi.org/10.1038/nature13967.
Oehlers, Stefan H., Mark R. Cronan, Ninecia R. Scott, Monica I. Thomas, Kazuhide S. Okuda, Eric M. Walton, Rebecca W. Beerman, Philip S. Crosier, and David M. Tobin. “Interception of host angiogenic signalling limits mycobacterial growth.” Nature 517, no. 7536 (January 29, 2015): 612–15. https://doi.org/10.1038/nature13967.
Cambier, C. J., Kevin K. Takaki, Ryan P. Larson, Rafael E. Hernandez, David M. Tobin, Kevin B. Urdahl, Christine L. Cosma, and Lalita Ramakrishnan. “Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids.” Nature 505, no. 7482 (January 9, 2014): 218–22. https://doi.org/10.1038/nature12799.