Tuberculosis is almost a uniquely human condition because, although the bacterium can infect a range of hosts, it only proceeds to transmission in humans and higher primates. Transmission is a consequence of the tissue response to the bacterium that is probably driven by bacterial components released by the intracellular bacilli. During the previous funding period we demonstrated that Mycobacterium releases its peripheral cell wall components into its host cell, and that these lipids are capable of spreading to neighboring, uninfected cells. We isolated and identified the major lipid species and, in a novel granuloma development model, determined that trehalose mycolates were the most bioactive. We have found that, under certain circumstances and in certain tissue sites, trehalose dimycolate (TDM) induces a destructive tissue response that is highly reminiscent of late stage granuloma breakdown in humans. In this current application we propose to characterize the host gene expression profile in late-stage, degenerative human tuberculosis granulomas, and compare and contrast this with the nature and mechanisms behind the murine response to bacterial cell components in our granuloma model to delineate the tissue reaction that leads to transmission.
The specific aims of this proposal are as follows: 1. What is the transcriptional profile within the human granuloma during necrosis and transmission? We intend to determine the gene expression profiles in specific regions within late stage human granulomas during caseation and necrosis. This should determine the """"""""major players"""""""" in driving tissue destruction leading to transmission. 2. The development of a tissue breakdown model to identify the role(s) of different factors involved in tissue remodeling and granuloma dissolution. Murine tuberculosis granulomas do not progress to caseation the way human granulomas do however we can manipulate the response to bacterial cell wall components to give a much more comparable result. We intend to validate experimentally the factors implicated in specific aim #1 in driving the tissue breakdown. 3. How is TDM recognized by the innate immune system? The recognition of the potent biomodulator TDM is dependent on both the host receptors, and the mechanism of presentation of TDM. We propose to identify the receptor(s) involved and elucidate their cellular and tissue distribution, and the signaling pathways through which they operate. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055936-13
Application #
7448474
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Peavy, Hannah H
Project Start
1995-09-30
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
13
Fiscal Year
2008
Total Cost
$386,333
Indirect Cost
Name
Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Tan, Shumin; Yates, Robin M; Russell, David G (2017) Mycobacterium tuberculosis: Readouts of Bacterial Fitness and the Environment Within the Phagosome. Methods Mol Biol 1519:333-347
Nazarova, Evgeniya V; Russell, David G (2017) Growing and Handling of Mycobacterium tuberculosis for Macrophage Infection Assays. Methods Mol Biol 1519:325-331
Cumming, Bridgette M; Rahman, Md Aejazur; Lamprecht, Dirk A et al. (2017) Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection. PLoS Pathog 13:e1006389
Lee, Wonsik; VanderVen, Brian C; Walker, Suzanne et al. (2017) Novel protein acetyltransferase, Rv2170, modulates carbon and energy metabolism in Mycobacterium tuberculosis. Sci Rep 7:72
VanderVen, Brian C; Huang, Lu; Rohde, Kyle H et al. (2016) The Minimal Unit of Infection: Mycobacterium tuberculosis in the Macrophage. Microbiol Spectr 4:
Liu, Yancheng; Tan, Shumin; Huang, Lu et al. (2016) Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J Exp Med 213:809-25
Russell, David G (2016) The ins and outs of the Mycobacterium tuberculosis-containing vacuole. Cell Microbiol 18:1065-9
Tan, Shumin; Russell, David G (2015) Trans-species communication in the Mycobacterium tuberculosis-infected macrophage. Immunol Rev 264:233-48
Subbian, Selvakumar; Tsenova, Liana; Kim, Mi-Jeong et al. (2015) Lesion-Specific Immune Response in Granulomas of Patients with Pulmonary Tuberculosis: A Pilot Study. PLoS One 10:e0132249
Podinovskaia, Maria; Russell, David G (2015) Detection and quantification of microbial manipulation of phagosomal function. Methods Cell Biol 126:305-29

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