The Influence of Chronic Infection with Mycobacterium tuberculosis on the Development of Protective Memory T cell Responses

Summary

This project will define the factors that are important for the development of memory T cell responses after chronic bacterial infection.

Supervisor(s)

Dr Jamie Triccas, Professor Warwick J Britton

Research Location

Camperdown - Central Clinical School

Program Type

PHD

Synopsis

Tuberculosis (TB), a chronic bacterial infection caused by Mycobacterium tuberculosis, remains a major cause of mortality and morbidity. The current vaccine in use, BCG, has been unable to limit the spread of the disease, with 2 million TB deaths worldwide each year. Despite the global health threat posed by TB and the need for new generation vaccines, we are hindered by our lack of knowledge of the fundamental immune mechanisms that are required to protect against TB. In addition, there is little information on the nature of T cell behaviour in response to chronic bacterial infections. This project aims to improve our understanding of how the immune system interacts with mycobacteria, in the hope that this information can be used to aid development of new generation anti-TB vaccines. The first section of the project will compare immunity induced by virulent M. tuberculosis and the BCG vaccine, in order to determine if any ‘deficiencies' exist in BCG-induced immunity, and to characterise in detail how M. tuberculosis infection impacts on the immune system. By using multi-parameter flow cytometry and adoptive T cell transfer systems, the project will examine the initial kinetics of T cell activation, migratory patterns of activated T cells and generation of T cell memory after BCG or M. tuberculosis infection. We will be particularly interested in comparing and contrasting the pattern of responses of both CD4+ and CD8+ T cells, as a detailed analysis of these cells has not been previously performed in response to chronic bacterial infection. Additional experiments will also examine the influence of antigen persistence on T cell immunity, using mycobacterial strains engineered to modulate the expression and maintenance of antigen in vivo. The project will also address the hypothesis that enhancing the function of antigen presenting cells (APCs) and the survival of T cells can improve the generation and maintenance of vaccine-induced memory T cell responses. This will be performed by constructing recombinant forms of the BCG expressing cytokines or growth factors important for theses processes. Experiments will investigate the influence on APC numbers and T cell responses by the recombinant vaccines, with a particular emphasis on the generation of memory T cells. The project will also investigate if the rBCG strains can protect mice against challenge with M. tuberculosis, using models of aerosol infection established in the laboratory.

Additional Information

Techniques and resources: Culture of pathogenic bacteria (PC3 laboratory); Recombinant DNA technology; animal handling; vaccination strategies; various immunological techniques(cell isolation, ELISPOT, multi-parameter flow cytometry).

Keywords

tuberculosis, immune response, lung infection, memory T cells, Vaccination

Opportunity ID

The opportunity ID for this research opportunity is: 1201

Other opportunities with Dr Jamie Triccas

• To identify new mechanisms used by pathogenic mycobacteria to secrete virulence proteins
• The molecular basis of persistence in clinical P. aeruginosa strains from cystic fibrosis patients

Other opportunities with Professor Warwick J Britton

• Interaction of viral and tuberculosis infections in the lung
• Role of LIGHT in the immunological control of cancer