Grant: $634,810 - National Institutes of Health - Jul. 22, 2009
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Award Description: The greatest barrier to development of efficacious vaccines against tuberculosis is the ability of Mycobacterium tuberculosis to persist and to cause progressive infection despite development of an adaptive immune response. While partially-efficacious vaccines may result from optimal selection of antigens, adjuvants, and delivery systems, major progress against tuberculosis will require novel approaches to enhancing resistance, based on overcoming or bypassing the mechanisms used by M. tuberculosis to evade adaptive immune responses. To identify and characterize those mechanisms, we have developed novel tools for use in a mouse model of immunity to M. tuberculosis to discover and characterize mechanisms that limit the efficacy of the adaptive immune response to M. tuberculosis. We have developed a system using a monoclonal antibody that recognizes a specific peptide:MHC II complex and several recombinant strains of M. tuberculosis, to test the hypothesis that M. tuberculosis inhibits MHC II antigen presentation in vivo, and to test the hypothesis that M. tuberculosis transfers antigens to uninfected cells as an immune evasion strategy. We have also developed a system using CD4+ T cells from a unique line of mice with a transgenic T cell antigen receptor specific for M. tuberculosis Ag85B, and have discovered that downregulation of the gene encoding Ag85B during the chronic stage of M. tuberculosis infection is accompanied by diminished in vivo CD4+ T cell responses to Ag85B. Taken together, these results suggest that M. tuberculosis may modulate expression of antigen genes as a means of avoiding recognition and elimination by CD4+ effector T cells. We also developed a method for visualization and localization of M. tuberculosis-infected cells and CD4+ T cells in the lungs, and have found that a minority of M. tuberculosis-infected cells in the lungs are in direct contact with CD4+ T cells, which supports the hypothesis that CD4+ T cells recognize M. tuberculosis-infected cells poorly at the site of infection. In this application, we propose experiments to test the general hypothesis that interactions between M. tuberculosis-infected cells and antigen-specific CD4+ T cells in the lungs are defective, and that this contributes to persistence of the infection. We will test the specific hypothesis that defective interactions between M. tuberculosis-infected cells and CD4+ T cells during chronic infection are due to a combination of: 1) M. tuberculosis inhibition of antigen presentation by infected cells; 2) decreased expression of M. tuberculosis antigens during the chronic stage of infection; and 3) transfer of M. tuberculosis antigens from infected cells to neighboring uninfected cells in granulomas, allowing uninfected cells to act as decoys to activate T cells at a distance from infected cells. Our proposed studies will provide unprecedented insight into the mechanisms used by M. tuberculosis to evade elimination by the mammalian adaptive immune response, and will guide future efforts to develop the means to increase human resistance to tuberculosis.
Project Description: We have determined that CD4+ T cell responses to M. tuberculosis Ag85B correlate with expression of the M. tuberculosis Ag85B gene in lungs of infected mice. We have generated the strains of bacteria to test the hypothesis that forced expression of Ag85B will increase responses of Ag85B-specific CD4+ T cells in vivo, and the experiments are underway to determine whether CD4+ T cell responses to Ag85B are enhanced in the lungs of mice infected with M. tuberculosis that over expresses Ag85B.
Jobs Summary: Two employees were retained so far as a consequence of this Award. One, a Research Technician (.40), would have had to be dismissed if it were not for the funds available on this Award. The other, an Associate Research Scientist (0.33), who has worked with the PI for 7 years, would either have had to be dismissed or would have had his salary reduced by half, if it were not for the funds from this Award. In addition, the Principal Investigator (22.10%) would have had to generate salary from other activities if it were not for these funds. If the PI were to have had to perform other work, it would have displaced another person who was retained as a consequence of this Award. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 22, 2009. Help expand these official descriptions using the wiki below.