Tuberculosis: mycobacterial pathogenesis and host susceptibility

Tuberculosis kills over 1.3 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.

Rebecca Beerman
Postion: Duke ASIST Office

Mark Cronan
Position: Group Leader, Max Planck Institute for Infection Biology, Berlin, Germany

Kim Dohlich
Position: Medical Student, University of Munster, Germany

Molly Matty
Position: Postdoctoral Fellow, Salk Institute
San Diego, CA

Stefan Oehlers
Position: Group Leader, University of Sydney

Allison Rosenberg
Position: MedThink SciComm

Joe Saelens
Position: Postdoctoral Fellow, Duke University
Durham, NC

Ninecia Scott
Position: Graduate Student, Washington University, St. Louis

Eric Walton
Position: Postdoctoral Fellow, Duke University
Durham, NC

Yuxia Zou
Position: Associate Professor, Chinese Academy of Sciences,
Qingdao, China

Representative Publications:

Google Scholar Profile

Cronan MR, Hughes EJ, Brewer WJ, Viswanathan G, Hunt EG, Singh B, Mehra S, Oehlers SH, Gregory SG, Kaushal D, Tobin DM (2021). A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization. Cell 184(7):1757-1774

Wang Y, Hsu AY, Walton EM, Park SJ, Syahirah R, Wang T, Zhou W, Ding C, Lemke AP, Zhang G, Tobin DM, Deng Q (2021). A robust and flexible CRISPR/Cas9 based system for neutrophil-specific gene inactivation in zebrafish. J Cell Sci doi: 10.1242/jcs.258574. Epub ahead of print.

Whitworth LJ, Troll R, Pagán AJ, Roca FJ, Edelstein PH, Troll M, Tobin DM, Phu NH, Bang ND, Thwaites GE, Thuong NTT, Sewell RF, Ramakrishnan L (2021). Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone. Proc Natl Acad Sci U S A 118(10):e2024852118.

Turner NA, Sweeney MI, Xet-Mull AM, Storm J, Mithani SK, Jones DB, Miles JJ, Tobin DM, Stout JE (2020). Cluster of Non-tuberculous Mycobacterial Tenosynovitis following Hurricane Relief Efforts. Clin Infect Dis doi: 10.1093/cid/ciaa1665. Epub ahead of print

McClean CM, Tobin DM (2020). Early cell-autonomous accumulation of neutral lipids during infection promotes mycobacterial growth. PLoS One15:e0232251.

Saelens JW, Viswanathan G, Tobin DM (2019). Mycobacterial evolution intersects with host tolerance. Front Immunol 10:528.

Matty MA, Knudsen DR, Walton EM, Beerman RW, Cronan MR, Pyle CJ, Hernandez RE, Tobin DM (2019). Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection. eLife 8 pii e39123.

Cronan MR, Matty MA, Rosenberg AF, Blanc L, Pyle CJ, Espenschied ST, Rawls JF, Dartois V, Tobin DM (2018). An explant technique for high-resolution imaging and manipulation of mycobacterial granulomas. Nature Methods 15:1097-1108.

Walton EM, Cronan MR, Cambier CJ, Rossi A, Marass M, Foglia MD, Brewer WJ, Poss KD, Stainier DYR, Bertozzi CR, Tobin DM (2018). Cyclopropane modification of trehalose dimycolate drives granuloma angiogenesis and mycobacterial growth through Vegf signaling. Cell Host & Microbe 24:514-525.

Jain SK, Tobin DM, Tucker EW, Venketaraman V, Ordonez AA, Jayashankar L, Siddiqi OK, Hammoud DA, Prasadarao NV, Sandor M, Hafner R, Fabry Z; NIH Tuberculous Meningitis Writing Group (2018). Tuberculous meningitis: a roadmap for advancing basic and translational research. Nat Immunol 19:521-525.

Alvarez MI, Glover LC, Luo P, Wang L, Theusch E, Oehlers SH, Walton EM, Tram TTB, Kuang YL, Rotter JI, McClean CM, Chinh NT, Medina MW, Tobin DM, Dunstan SJ, Ko DC (2017). Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci USA 114:E7746-E7755.

Oehlers SH, Cronan MR, Beerman RW, Johnson MG, Huang J, Kontos CD, Stout JE, Tobin DM (2017). Infection-induced vascular permeability aids mycobacterial growth. J Infect Dis 215:813-817.

Cronan MR, Beerman RW, Rosenberg AF, Saelens JW, Johnson MG, Oehlers SH, Sisk DM, Jurcic Smith KL, Medvitz NA, Miller SE, Trinh LA, Fraser SE, Madden JF, Turner J, Stout JE, Lee S, Tobin DM (2016). Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection. Immunity 45:861-76.

Beerman RW, Matty MA, Au GG, Looger LL, Choudhury KR, Keller PJ, Tobin DM (2015). Direct in vivo manipulation and imaging of calcium transients in neutrophils identifies a critical role for leading-edge calcium flux. Cell Reports 13:2107-17.

Cronan MR, Rosenberg AF, Oehlers SH, Saelens JW, Sisk DM, Smith KLJ, Lee S, Tobin DM (2015). CLARITY and PACT-based imaging of adult zebrafish and mouse for whole-animal analysis of infections. Dis Model Mech 8:1643-50.

Saelens JW, Lau-Bonilla D, Moller A, Medina N, Guzmán B, Calderón M, Herrera R, Sisk DM, Xet-Mull AM, Stout JE, Arathoon E, Samayoa B*, Tobin DM* (2015). Whole genome sequencing identifies circulating Beijing-lineage Mycobacterium tuberculosis strains in Guatemala and an associated urban outbreak. Tuberculosis 95:810-16.

Tenor J*, Oehlers SH*, Yang JL, Tobin DM**, Perfect JR** (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. doi:10.1128/mBio.01425-15

Wang L, Oehlers SH, Espenschied ST, Rawls JF, Tobin DM, Ko DC (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.

Tobin, DM. (2015). Host-Directed Therapies for Tuberculosis, Cold Spring Harb Perspect Med 5(10) pii: a021196. doi: 10.1101/cshperspect.a021196.

Oehlers SH, Cronan MR, Thomas MI, Okuda KS, Walton EM, Beerman RW, Crosier PS, Tobin DM (2015). Interception of host angiogenic signalling limits mycobacterial growth. Nature 517: 612-15.

Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CC, Ramakrishnan L (2014). Mycobacteria manipulate macrophage recruitment through coordinate use of membrane lipids. Nature 505(7482):218-22

Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou Y, Bang ND, Chau TTH, Vary JC, Hawn TR, Dunstan SJ, Farrar JJ, Thwaites GE, King M-C, Serhan CN, Ramakrishnan L (2012). Genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148: 434-446.

Tobin DM, Vary JC, Ray JP, Walsh GS, Bang ND, Dunstan SJ, Hagge DA, Khadge S, King MC, Hawn TR, Moens CB, Ramakrishnan L. (2010). The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140(5):717-30.

For a complete list of publications, click here.