Human tuberculosis (TB) susceptibility is a complex and polygenic trait. The long-term objective of this research is to determine the extent of candidate genes in human innate immunity contributing to human TB susceptibility and the potential host-pathogen interactions. Our internationally collaborative team with a recently established TB sentinel surveillance network in China combines the resources of an ideal target population with an advanced investigative capacity to address the research objective. An important aspect of this study is to avoid the bias associated with our previous work in this field by utilizing several recent advances in Mycobacterium tuberculosis infection diagnosis. The following research lines are proposed. 1. The candidate gene-based association study has been considered more powerful than the linkage study in determination of genetic susceptibility to human complex disease such as TB. Two complementary approaches of the association study: the population-based case-control study and the family-based transmission-disequilibrium test (TDT), will be combined to explore associations between human TB susceptibility and candidate genes encoding M. tuberculosis extracellular receptors (toll-like receptors) and intracellular receptor (NOD2), which play an important role in human innate immunity against TB. 2. State-of-the-art molecular strategies will be used to conduct genome-level screening for common and rare nonsynonymous genetic variants in the candidate genes which are potentially associated with TB susceptibility in a previously unexplored target population. 3. All M. tuberculosis isolates from TB cases in this study will be molecularly characterized to test the hypothesis that distinct pathogen genotypes are nonrandomly associated with specific host genotypes. A particular interest will be placed on our recent finding in China, the """"""""Shandong cluster"""""""", which is a widely disseminated M. tuberculosis cluster with increased likelihoods of drug-resistance and transmissibility.

Public Health Relevance

Tuberculosis (TB) is the most deadly infectious disease in the world, and accounts for 2 million deaths and 8 million new cases worldwide each year. TB control measures have been complicated by the increased prevalence of HIV/TB co-infection and drug-resistant bacteria. Our research at genome level will improve the understanding of the interaction between the host and pathogen, which may shed light on alternative strategies for TB treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075465-02
Application #
7646446
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (50))
Program Officer
Lacourciere, Karen A
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$80,789
Indirect Cost
Name
Shandong Provincial Chest Hospital
Department
Type
DUNS #
547721852
City
Jinan
State
Country
China
Zip Code
25001-3
Deng, Yunfeng; Li, Yan; Wang, Fengtian et al. (2015) Tuberculosis prevention in healthcare workers in China 10?years after the severe acute respiratory syndrome pandemic. ERJ Open Res 1:
Jing, Hui; Tan, Wanming; Deng, Yunfeng et al. (2014) Diagnostic delay of pulmonary nontuberculous mycobacterial infection in China. Multidiscip Respir Med 9:48
Jing, Hui; Wang, Haiying; Wang, Yan et al. (2012) Prevalence of nontuberculous mycobacteria infection, China, 2004-2009. Emerg Infect Dis 18:527-8
Nguyen, Yen H; Ma, Xin; Qin, Lidong (2012) Rapid identification and drug susceptibility screening of ESAT-6 secreting Mycobacteria by a NanoELIwell assay. Sci Rep 2:635
Li, X; Wang, H; Jing, H et al. (2012) Population-based surveillance of extensively drug-resistant tuberculosis in Shandong Province, China. Int J Tuberc Lung Dis 16:612-4
Zhao, J; Wang, Y; Wang, H et al. (2011) Low agreement between the T-SPOTĀ®.TB assay and the tuberculin skin test among college students in China. Int J Tuberc Lung Dis 15:134-6
Deng, Yunfeng; Wang, Yan; Wang, Junling et al. (2011) Laboratory-based surveillance of extensively drug-resistant tuberculosis, China. Emerg Infect Dis 17:495-7