Tuberculosis (TB) remains the leading infectious cause of global mortality. The emergence of drug resistant TB and a deadly synergy with HIV seen in recent years highlight the need for a better understanding of TB transmission and pathogenesis. The long term objectives of our project are: 1) to identify underlying genetic factors of Mycobacterium tuberculosis important to the pathogenesis and the epidemiology of TB and 2) to provide targets for the development of more efficient vaccine and therapeutical agents for TB prevention and control. Our hypothesis for the present project is that survival of successful bacterial pathogens not only depends on their ability to alter global patterns of gene expression in response to the changing environments during infection, but also depends on the presence or absence of certain genes in the bacteria that play an important role in virulence, and that loss or gain of such genes in clinical strains of M. tuberculosis is associated with their infectivity and pathogenicity.
Our specific aims and the related experimental strategies are: 1) to determine genomic variation among M. tuberculosis strains associated with different epidemiological and clinical characteristics by genomic subtraction and to identify DNA unique to epidemiologically and clinically successful strains of M. tuberculosis in comparison with epidemiologically and clinically less successful strains, and with already sequenced strains of M. tuberculosis, H37Rv and CDC 1551; 2) to assess the potential importance of the fragments identified by DNA subtraction to TB transmission and pathogenesis by screening for the presence or absence of the fragments in approximately 700 clinical isolates collected during a five year population-based molecular epidemiological study conducted in Arkansas; and the relative distribution of these subtraction products will be determined by epidemiological and clinical co-variates; and 3) to identify and to characterize genes contained in the subtraction products which are associated with TB transmission and pathogenesis, the flanking regions of the fragments identified by subtraction will be cloned for sequencing. By combining epidemiological information with molecular genetics, we are conducting a focused search for genes associated with transmission and pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051975-03
Application #
6608047
Study Section
Special Emphasis Panel (ZHL1-CSR-L (M4))
Program Officer
Sizemore, Christine F
Project Start
2001-09-30
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$322,283
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Yang, Zhenhua; Rosenthal, Mariana; Rosenberg, Noah A et al. (2011) How dormant is Mycobacterium tuberculosis during latency? A study integrating genomics and molecular epidemiology. Infect Genet Evol 11:1164-7
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