This K23 award will provide an opportunity for Dr. Horne to develop as an independent investigator in patient-oriented clinical research on genetic variation in innate immunity and susceptibility to tuberculosis (TB) infection. This career development application describes a comprehensive plan to accomplish the following goals: 1) assemble a cohort of patients in order to identify genetic, exposure-, and pathogen-related risk factors for TB infection, 2) develop expertise in host genetic variation and TB infection, 3) develop an understanding of the host innate immune response following an exposure to Mycobacterium tuberculosis (MTb), and 4) develop an independent clinical research career. These goals will be accomplished through mentorship by key personnel, didactic course work, instruction in practical laboratory skills, and participation in scientific meetings. We will assemble a cohort of patients in Seattle, Washington, who have a known TB exposure with the following specific aims: 1) thoroughly characterize clinical and exposure-related factors, identify MTb phylogenetic lineage from the index case, and use these factors to develop a risk factor model for TB infection;and 2) perform a nested case- control study in unrelated subjects to determine whether single nucleotide polymorphisms (SNPs) in candidate genes related to innate immunity are associated with TB infection. In our analysis of genetic associations, we will adjust for significant clinical, exposure and pathogen-related risk factors identified in Aim 1. We will confirm genetic associations in a previously collected family- based cohort. This study is novel for the outcome of TB infection and the inclusion of MTb lineage. The rich academic environment at the University of Washington is ideal for Dr. Horne's training and has allowed him to assemble an advisory committee whose members possess expertise in innate immunology, MTb phylogenetics, genetic epidemiology, biostatistics, risk factor modeling and TB transmission. Dr. Hawn, the primary mentor, is a successful and recognized expert in innate immunity, especially pathogen recognition receptors and associated pathways. He has investigated the role of Toll-like receptors (TLRs) in mycobacterial infection in functional and genetic association studies. Dr. Peter Small, co-mentor, is an internationally recognized expert in MTb phylogenetics. /Relevance TB infection, compared to TB disease, is an understudied area and little is known about host genetics and susceptibility to TB infection. TB is estimated to infect one-third of the global population and findings from this study could be important to TB vaccine development. Findings may also have relevance to other infectious diseases.

Public Health Relevance

/Relevance TB infection, compared to TB disease, is an understudied area and little is known about host genetics and susceptibility to TB infection. TB is estimated to infect one-third of the global population and findings from this study could be important to TB vaccine development. Findings may also have relevance to other infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI085036-04
Application #
8460546
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Jacobs, Gail G
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$127,521
Indirect Cost
$9,446
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ghassemieh, Bijan J; Attia, Engi F; Koelle, David M et al. (2016) Latent Tuberculosis Infection Test Agreement in the National Health and Nutrition Examination Survey. Am J Respir Crit Care Med 194:493-500
LaCourse, Sylvia M; Cranmer, Lisa M; Matemo, Daniel et al. (2016) Tuberculosis Case Finding in HIV-Infected Pregnant Women in Kenya Reveals Poor Performance of Symptom Screening and Rapid Diagnostic Tests. J Acquir Immune Defic Syndr 71:219-27
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
Horne, David J; Narita, Masahiro; Spitters, Christopher L et al. (2013) Challenging issues in tuberculosis in solid organ transplantation. Clin Infect Dis 57:1473-82
Arentz, Matthew; Pavlinac, Patricia; Kimerling, Michael E et al. (2012) Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review. PLoS One 7:e47370
Horne, David J; Randhawa, April K; Chau, Tran T H et al. (2012) Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis. J Infect Dis 205:586-94
Baker, Allison R; Qiu, Feiyou; Randhawa, April Kaur et al. (2012) Genetic variation in TLR genes in Ugandan and South African populations and comparison with HapMap data. PLoS One 7:e47597
Horne, David J; Campo, Monica; Ortiz, Justin R et al. (2012) Association between smoking and latent tuberculosis in the U.S. population: an analysis of the National Health and Nutrition Examination Survey. PLoS One 7:e49050
Horne, D J; Spitters, C; Narita, M (2011) Experience with rifabutin replacing rifampin in the treatment of tuberculosis. Int J Tuberc Lung Dis 15:1485-9, i
Nahid, Payam; Horne, David J; Jarlsberg, Leah G et al. (2011) Racial differences in tuberculosis infection in United States communities: the coronary artery risk development in young adults study. Clin Infect Dis 53:291-4

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