Role of tuberculosinyl metabolites in M. tuberculosis virulence Abstract Among all types of mycobacteria, Mycobacterium tuberculosis is the world's most prevalent and deadly pathogen. To find the particular molecules that enable its pathogenicity, we compared all detectable lipids in M. tuberculosis to those in a non-pathogenic vaccine strain (BCG). This subtractive screen identified a previously type of molecule called tuberculosinyl adenosine (TbAd) as well as the genes (Rv3377c, Rv3378c) that produce it. Although TbAd was overlooked in a century of tuberculosis research, our preliminary data show that TbAd is one of the most abundant lipids and is produced as six structurally related subfamilies. Published data show that M. tuberculosis is unique among mycobacteria in its ability to survive within the phagosomes of infected macrophages, based in its blockade of acid-mediated bacterial killing by macrophages. Our preliminary data show that TbAd is sufficient to block acidification of macrophage phagosomes. Therefore, we posit that TbAd and related tuberculosinyl metabolites are the long sought molecules that influence M. tuberculosis' unique ability to escape intracellular death. Here we propose to discover new tuberculosinyl metabolites in M. tuberculosis and determine their natural structures. Using synthetic TbAd and human macrophages, we will determine the cellular mechanism by which TbAd selectively inhibits phagosome acidification, while still allowing M. tuberculosis to be taken up into its phagosomal niche. Using M. tuberculosis lacking the biosynthetic enzymes (Rv 3378c, Rv3377c), we will measure the influence of TbAd in the outcome of natural infections. Last, we will test tuberculosinyl metabolites as targets for new diagnostic tests for human tuberculosis. Several features suggest that TbAd and TbAd-specific antibodies could be a highly specific chemical marker or infection. TbAd is abundantly secreted by M. tuberculosis, but is lacking in other pathogens that mimic tuberculosis. Therefore, we will detect TbAd and TbAd specific antibodies in serum and urine from a well-characterized patient cohort in Lima, Peru and in mice.

Public Health Relevance

Role of tuberculosinyl metabolites in M. tuberculosis virulence Relevance To create rapid tests for diagnosing tuberculosis, we will systematically screen the infecting organism for characteristic molecules that differ from molecules in other bacteria. To intervene in tuberculosis disease, we will pinpoint the molecules that allow it to survive in human macrophages. Better diagnosis and treatment of TB is needed to contain the worldwide epidemic, which killed more than one million people last year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116604-04
Application #
9416068
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Lacourciere, Karen A
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Layre, Emilie; Moody, D Branch (2013) Lipidomic profiling of model organisms and the world's major pathogens. Biochimie 95:109-15