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.
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.
|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:|
|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|
|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|
|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:|
|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|
|Ng, Tony W; Saavedra-Ávila, Noemí A; Kennedy, Steven C et al. (2015) Current efforts and future prospects in the development of live mycobacteria as vaccines. Expert Rev Vaccines 14:1493-507|
|Panas, Michael W; Sixsmith, Jaimie D; White, KeriAnn et al. (2014) Gene deletions in Mycobacterium bovis BCG stimulate increased CD8+ T cell responses. Infect Immun 82:5317-26|
|Sixsmith, Jaimie D; Panas, Michael W; Lee, Sunhee et al. (2014) Recombinant Mycobacterium bovis bacillus Calmette-Guérin vectors prime for strong cellular responses to simian immunodeficiency virus gag in rhesus macaques. Clin Vaccine Immunol 21:1385-95|
|Carreño, Leandro J; Kharkwal, Shalu Sharma; Porcelli, Steven A (2014) Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy 6:309-20|
|Venkataswamy, Manjunatha M; Ng, Tony W; Kharkwal, Shalu S et al. (2014) Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells. PLoS One 9:e108383|
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