Effective host immunity to Mycobacterium tuberculosis is dependent on T cell-mediated responses against antigens of the bacillus. Our recent work has shown that M.tuberculosis encodes In its genome pathways that promote evasion or subversion of host immunity, and that these interfere with effective vaccination by live, attenuated mycobacterial strains. In previous work, we have identified multiple immune evasion genes and have demonstrated that their inactivation or deletion can lead to more immunogenic, attenuated live mycobacterial vaccines. In this project, we will build on this background to develop novel live M. tuberculosis strains that generate enhanced T cell responses and more robust protective immunity in infected animals. Mutations will also be introduced to eliminate virulence even in the setting of immunodeficiency, thus creating vaccine strains that will in principle be safe for widespread use in human populations. In addition, we will use the incorporation of chemical adjuvant into live mycobacterial vaccine strains and several approaches to boosting of secondary responses to further enhance vaccine-induced protection against tuberculosis.
Three specific aims are proposed: 1) Assess the impact of mutations In M. tuberculosis that enhance apoptosis of infected host cells on T cell responses;2) Identify and characterize mutants of M. tuberculosis that enhance antigen presentation by MHC class 11;3) Combine genetic modifications with chemical adjuvant and boosting strategies to enhance T cell response and protective efficacy induced by attenuated M. tuberculosis vaccine strains. The long term goal of these studies is to establish principles that will lead to safer and more effective live M. tuberculosis vaccines that will contribute to controlling the global burden of tuberculosis and to reducing the emergence of multidrug resistant strains. This project relates to the overall goals of this program project by seeking to improve the immunogenicity of live attenuated M. tuberculosis vaccines, and by establishing correlates of protection through the analysis of specific cellular immune responses. Extensive interactions with other components of the P01 funded program are proposed, and the project will benefit significantly from the various core resources supported by the P01.

Public Health Relevance

This proposal is an integral component of a program that aims to understand in greater detail the mechanisms by which Mycobacterium tuberculosis evades host immunity to cause serious disease and mortality. The goal of the research is to establish principles that will enable the design and construction of better vaccines for the prevention of tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Albert Einstein College of Medicine
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Glass, Lisa N; Swapna, Ganduri; Chavadi, Sivagami Sundaram et al. (2017) Mycobacterium tuberculosis universal stress protein Rv2623 interacts with the putative ATP binding cassette (ABC) transporter Rv1747 to regulate mycobacterial growth. PLoS Pathog 13:e1006515
Johnson, Alison J; Kennedy, Steven C; Lindestam Arlehamn, Cecilia S et al. (2017) Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4+ T Cells. Infect Immun 85:
Kunnath-Velayudhan, Shajo; Goldberg, Michael F; Saini, Neeraj K et al. (2017) Transcriptome Analysis of Mycobacteria-Specific CD4+ T Cells Identified by Activation-Induced Expression of CD154. J Immunol 199:2596-2606
Carreño, Leandro J; Saavedra-Ávila, Noemí A; Porcelli, Steven A (2016) Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents. Clin Transl Immunology 5:e69
Phuah, Jiayao; Wong, Eileen A; Gideon, Hannah P et al. (2016) Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques. Infect Immun 84:1301-11
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
Foreman, Taylor W; Mehra, Smriti; LoBato, Denae N et al. (2016) CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection. Proc Natl Acad Sci U S A 113:E5636-44
Olsen, Aaron; Chen, Yong; Ji, Qingzhou et al. (2016) Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines. MBio 7:
Vergnolle, Olivia; Xu, Hua; Tufariello, JoAnn M et al. (2016) Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore Biosynthesis. J Biol Chem 291:22315-22326
Saini, Neeraj K; Baena, Andres; Ng, Tony W et al. (2016) Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47. Nat Microbiol 1:16133

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