Tuberculosis Research Program
Location: Centenary Institute of Cancer Medicine and Cell Biology
Lab members: Dr Manuela Florido: Vaccine deveelopment and interaction of influenza and tuberculosis Dr Mainthain Palendira: Human cancer viral immunology
Research approach equipment: T cell responses to Mycobacterium tuberculosis and viruses in humans and during murine tuberculosis. Vaccine development and experimental tuberculosis infection. Macrophage responses to infection Immunogenetics: genetic susceptibility to Tuberculosis Drug development against mycobacteria
Cellular immune responses to influenza and mycobacterial co-infections in the lung
Primary supervisor: Warwick Britton
Mycobacterium tuberculosis and Influenza A virus are two of the most important respiratory pathogens of humans. Tuberculosis remains a major cause of death and morbidity throughout the world. Protection against M. tuberculosis infection in the lung is dependent on activation of CD4 and CD8 T cells in mediastinal lymph nodes and their recruitment back to the lung. Many other viral respiratory pathogens stimulate T cell responses in the lung and the interaction between different infections may influence the immune response and effectiveness of vaccines against either mycobacterial or viral pathogens.
Previous results using a mouse model of pulmonary co-infection with M. bovis BCG and a mouse adapted influenza A virus strain showed that co-infection with the influenza A virus had a detrimental effect on the T cell response to BCG and led to increased accumulation of cells and delayed mycobacterial clearance in the lung. In this project we will address the role of chemokines and cytokines, in particular type I interferons, in the effects induced in the lung by co-infection with BCG and influenza A virus. Furthermore recombinant influenza A viruses expressing dominant CD4 and CD8 T cell epitopes from Mycobacterium tuberculosis have been generated. We will analyse the ability of these viruses to induce T cell responses to those M. tuberculosis specific epitopes. Tcr transgenic mice whose lymphocytes recognize the dominant CD4 T cell epitope in mycobacteria and tetramers to recognize specific CD8 T cells are available. These will allow us to determine how mycobacterium-specific CD4 and CD8 memory T cell responses generated by the viral infections influence T cell responses to primary infection with M. tuberculosis or the vaccine strain M. bovis BCG. The nature of the response to the different pathogens and the effect of these responses on protection against subsequent mycobacterial challenge will be examined. These studies are relevant to the design and implementation of more effective vaccines against tuberculosis using recombinant viral and mycobacterial vectors.
Experimental infections of mice with BCG and mouse adapted influenza A virus strains, cellular immunology, cytokine and chemokine analysis, flow cytometry including tetramer analysis.