Tuberculosis is the leading cause of death from infectious diseases worldwide, with increasing consequences due to the HIV epidemic. Infection and disease are caused by the intracellular bacterial pathogen Mycobacterium tuberculosis. The existing vaccine, BCG, has marginal efficacy and drug therapies are long and complex leading to noncompliance and the rapid spread of multi-drug resistant bacteria. Additionally, in the developed world, the increasing use of TNF blockade for the treatment of rheumatologic and immunological conditions has led to the activation of tuberculosis in these patients. In the face of a complex immune response, mycobacteria can persist indefinitely in granulomas, tight aggregates of highly differentiated macrophages and other immune cells. As with most infectious diseases, the exact impact of the different components of host immunity on tuberculosis infection and disease are not well understood. To better understand the host responses to tuberculous infections, we will take advantage of the fact that Mycobacterium marinum, a close relative of M. tuberculosis, is a natural pathogen of zebrafish, causing a tuberculosis-like disease with all the basic pathologic features of human tuberculosis Zebrafish are genetically tractable vertebrates that are used as models of disease and development. We have exploited the optical transparency and the genetic tractablility of zebrafish embryos and larvae to monitor and modulate host-pathogen interactions of tuberculosis in real time. Due to our ability to perform real-time imaging of the individual steps of infection, we have been able to determine the precise steps at which key host immune determinants (e.g. TNF) and bacterial virulence determinants act during pathogenesis. We will combine a variety of molecular and genetic techniques to intercept the expression of host immune functions so as to determine their impact on the individual steps and final outcomes of tuberculosis by a variety of real- time microscopy techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054503-07
Application #
7617152
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-04-15
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
7
Fiscal Year
2009
Total Cost
$377,636
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Petrie, Timothy A; Strand, Nicholas S; Yang, Chao-Tsung et al. (2014) Macrophages modulate adult zebrafish tail fin regeneration. Development 141:2581-91
Cambier, C J; Takaki, Kevin K; Larson, Ryan P et al. (2014) Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505:218-22
Tobin, David M; Roca, Francisco J; Ray, John P et al. (2013) An enzyme that inactivates the inflammatory mediator leukotriene b4 restricts mycobacterial infection. PLoS One 8:e67828
Takaki, Kevin; Davis, J Muse; Winglee, Kathryn et al. (2013) Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in zebrafish. Nat Protoc 8:1114-24
Ramakrishnan, Lalita (2012) Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 12:352-66
Takaki, Kevin; Cosma, Christine L; Troll, Mark A et al. (2012) An in vivo platform for rapid high-throughput antitubercular drug discovery. Cell Rep 2:175-84
Tobin, David M; Roca, Francisco J; Oh, Sungwhan F et al. (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434-46
Adams, Kristin N; Takaki, Kevin; Connolly, Lynn E et al. (2011) Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145:39-53
Volkman, Hannah E; Pozos, Tamara C; Zheng, John et al. (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327:466-9
Tobin, David M; Vary Jr, Jay C; Ray, John P et al. (2010) The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717-30

Showing the most recent 10 out of 22 publications