Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The innate immune system enables the host to differentiate self from invading microbes, discriminate among pathogens, and initiate a cascade of inflammation. These functions, which are orchestrated by Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs), regulate bacterial killing and influence formation of the adaptive immune response as well as host survival. Although these gene families are critical mediators of the immune response to pathogens, the influence of common TLR or NLR polymorphisms on susceptibility to infection in humans is poorly understood. Over the past 10 years, my research goals have been to understand the genetic and immunologic factors that influence human susceptibility to infections such as tuberculosis and to use this knowledge to design more effective vaccines and therapies. These projects include human genetic case-control studies which examine whether allelic variants of innate immunity genes are associated with human infections. These association studies are coupled with mechanistic experiments designed to determine which molecular and cellular responses are regulated by these variants.
The research aims of this proposal are to understand the clinical significance of variation of macrophage and pulmonary innate immune responses with molecular, cellular, and human genetic models. My mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity. Currently, there are 7 trainees working in my laboratory and each is examining a different aspect of the role of innate immunity polymorphisms in susceptibility to infection. We hypothesize that common variants of innate immunity genes regulate the immune response to pulmonary pathogens. We recently identified several polymorphisms in TOLLIP, a gene which regulates TLR-signaling, that are associated with susceptibility to Mycobacterium tuberculosis (MTb).
In Aim 1, we will examine the mechanism of how these TOLLIP polymorphisms regulate cellular function in response to infection with MTb.
In Aim 2, we will examine which aspects of the immune response to MTb are regulated by TOLLIP.
These research aims will be coordinated with a mentoring aim to develop a centralized innate immunity bioassay bank that can be utilized by all trainees in the laboratory. Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine.
The research aims of this proposal are to examine how variation of innate immunity genes regulates the pulmonary immune response to tuberculosis. The mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity.

Public Health Relevance

Despite the discovery of the tuberculosis bacillus over 100 years ago and the availability of effective drugs for over 50 years, there remain a number of formidable challenges for controlling Mycobacterium tuberculosis including understanding the mechanisms of host resistance and how to develop a more effective vaccine. The research aims of this proposal are to examine how variation of innate immunity genes regulates the pulmonary immune response to tuberculosis. The mentoring goals are to provide a dynamic scientific environment with resources to foster the careers of clinician scientists in patient-oriented research related to genetics and innate immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AI089794-05
Application #
8690745
Study Section
Microbiology and Infectious Diseases Research Committee (MID)
Program Officer
Prograis, Lawrence J
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Seshadri, C; Thuong, N T T; Mai, N T H et al. (2017) A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis. Genes Immun 18:8-14
Ford, Emily S; Horne, David J; Shah, Javeed A et al. (2017) Species-Specific Risk Factors, Treatment Decisions, and Clinical Outcomes for Laboratory Isolates of Less Common Nontuberculous Mycobacteria in Washington State. Ann Am Thorac Soc 14:1129-1138
Shah, Javeed A; Musvosvi, Munyaradzi; Shey, Muki et al. (2017) A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis. Am J Respir Crit Care Med 196:502-511
Shah, Javeed A; Berrington, William R; Vary Jr, James C et al. (2016) Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist. J Infect Dis 213:1189-97
Horne, David J; Graustein, Andrew D; Shah, Javeed A et al. (2016) Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection. J Infect Dis 214:1260-7
Seshadri, Chetan; Lin, Lin; Scriba, Thomas J et al. (2015) T Cell Responses against Mycobacterial Lipids and Proteins Are Poorly Correlated in South African Adolescents. J Immunol 195:4595-603
Hawn, Thomas R; Shah, Javeed A; Kalman, Daniel (2015) New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics. Immunol Rev 264:344-62
Campo, Monica; Randhawa, April K; Dunstan, Sarah et al. (2015) Common polymorphisms in the CD43 gene region are associated with tuberculosis disease and mortality. Am J Respir Cell Mol Biol 52:342-8
Graustein, A D; Horne, D J; Arentz, M et al. (2015) TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam. Tuberculosis (Edinb) 95:190-6

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