This proposal seeks to understand in greater detail the mechanisms by which Mycobacterium tuberculosis blocks the priming of effective host immunity, with the ultimate goal of using this information to create more effective live vaccine strains. Previous work identified multiple mycobacterial genes involved in blocking apoptosis of infected host cells, which is intimately linked to the ability of the pathogen to prevent presentation of its antigens by MHC class I. Extensive preliminary work has also identified genes in M. tuberculosis that interfere with MHC class II antigen presentation, and genes that block production of key cytokines. A major goal of this proposal is to construct safely attenuated strains of M. tuberculosis in which specific immune evasion genes have been deleted, thus creating more effective vaccines for priming of anti- mycobacterial immunity. The approach involves identifying the most potent anti- apoptotic genes from a group of four candidates that have already been partially characterized, and combining mutations in these with strongly attenuating auxotrophy mutations to eliminate virulence. Precise mutations in the genes of interest will be created using allelic exchange mediated by specialized transducing phages, a methodology that is well established in the laboratory of the PI and his collaborators. The potency of candidate vaccine strains will be further enhanced by incorporating additional mutations in genes that interfere with MHC class II presentation, or with production of IL-12p70 or TNF. Immunological studies of CD4 and CD8 T cell priming by candidate vaccine strains will be carried out in mouse models, allowing identification of the most favorable combinations of specific gene deletions to advance into preclinical vaccination studies in rodents. Studies of the induction of stable T cell memory by candidate vaccine strains will be performed in mice, and the impact of boosting primary responses with mycobacterial proteins will also be initiated. Overall, the proposed studies will significantly advance our understanding of the host-pathogen interaction in tuberculosis, and contribute directly to vaccine development for prevention and control of this major human disease.

Public Health Relevance

This proposal aims to understand in greater detail the mechanisms by which Mycobacterium tuberculosis evades host immunity to cause serious disease and mortality. The information gained will be applied to the design and construction of better vaccines for the prevention of tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093649-02
Application #
8230473
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Parker, Tina M
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$415,000
Indirect Cost
$165,000
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Prados-Rosales, Rafael; Carreño, Leandro J; Weinrick, Brian et al. (2016) The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis. J Infect Dis 214:426-37
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Kozakiewicz, Lee; Chen, Yong; Xu, Jiayong et al. (2013) B cells regulate neutrophilia during Mycobacterium tuberculosis infection and BCG vaccination by modulating the interleukin-17 response. PLoS Pathog 9:e1003472

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