Mycobacterium tuberculosis (Mtb) is spread from person to person by aerosolized bacteria. After inhalation of small numbers of mycobacteria, the majority of healthy individuals become infected but do not progress to clinical tuberculosis. Granuloma formation in the lung is the pathological hallmark of this protective cellular immune response. Growth of tubercle bacilli is contained within developing lung granulomas and, while most are destroyed by the immune response, a number of bacilli enter a state of dormancy. T cells play a critical role in the protective immune response to M. tuberculosis and T cell dysfunction, such as seen in HIV infection, results either in the reactivation of dormant tubercle bacilli or in an inability to control primary infection. Little is known about how the immune response in lung granulomas controls M. tuberculosis growth and how the mycobacteria respond to the immune response. In this collaborative research project between investigators at Case Western Reserve University and Colorado State University, the murine model of aerosol infection with M. tuberculosis will be used to analyze granuloma formation in the lung to mycobacteria of differing degrees of virulence, to determine how the developing immune response affects the mycobacterial life cycle in the lung from rapidly growing to latent or recrudescent disease.
The specific aims are: 1. To characterize the dynamic changes in cellular composition and, chemokine and cytokine secretion in developing lung granulomas after aerogenic infection with M. bovis BCG, M. tuberculosis Erdman and a fast growing virulent M. tuberculosis clinical isolate, CSU-22. 2. To characterize the growth, metabolic activity, expression of selected genes (85B, 38kD), cell wall synthesis and virulence of the mycobacteria during granuloma development and latency. 3. To characterize the immune response and mycobacterial life cycle during recrudescent infection induced by treating mice with latent infection with anti-CD4 antibodies. These studies will define the host cellular immune response in the lung and determine how the immune response affects the mycobacterial life cycle. Such information will not only increase our understanding of the host-pathogen relationship in tuberculosis but also is necessary for the design of vaccines and immunotherapeutic interventions for tuberculosis.
