Research summary

Around one third of the world's population is infected with Mycobacterium tuberculosis resulting in approximately 2 million deaths from tuberculosis each year. The current vaccine against tuberculosis, bacille Calmette-Guerin (BCG), displays variable protective efficacy against the most prevalent disease form, pulmonary tuberculosis, and protection afforded by BCG is not life-long. Our research aims to understand how M. tuberculosis causes disease, and to develop novel and effective strategies to control infection.

Overview of research program

The research programme of the laboratory is divided into three main areas:

New vaccines to combat tuberculosis: Our focus in recent years has been to develop and assess live vaccines engineered to augment components of the immune response required for optimal anti-tuberculosis protective immunity. This has included the use of BCG strains engineered to secrete cytokines or chemokines that influence the number and activation state of dendritic cells (DCs) in order to enhance T cell immunity and pathogen elimination. Some of these vaccines have shown promise in our pre-clinical models of tuberculosis infection, and are undergoing further appraisal as candidates to control M. tuberculosis infection in humans. In parallel, attenuated strains of M. tuberculosis are being developed and tested for their vaccine potential.

Defining immunity induced by infection with Mycobacterium tuberculosis and new tuberculosis vaccine candidates: By the use of recombinant mycobacterial strains expressing reporter proteins and transgenic T cell systems, we are defining in detail the parameters associated with optimal protective immunity against tuberculosis. We are also using confocal microscopy and live-cell imaging to examine the relationship between mycobacteria and host cells. The information derived from the studies will aid selection of suitable mycobacterial strains for future development as anti-tuberculosis vaccines.

Elucidating strategies employed by pathogenic mycobacteria to survive within the host and promote virulence: We have used genetic screens to identify M. tuberculosis genes preferentially expressed within host cells. These studies have identified metabolic pathways that may be required for survival within the host. M. tuberculosis strains lacking in vivo-expressed genes are currently being developed to assess the contribution of the gene products to virulence. In addition, a selection of these in vivo-expressed genes are being investigated to identify the factors that regulate their expression and determine if the genes encode their predicted functions.

Major funding sources

NHMRC Biomedical Career Development Award (2006-2010): Identifying determinants of mycobacterial pathogenesis and understanding host immunity for the development of novel anti-tuberculosis vaccines. Triccas

NHMRC Project Grant (2009-2011). Chronic bacterial infection and the generation of T cell memory: implication for vaccination against tuberculosis. Triccas, Britton

NHMRC Project Grant (2008-2010). Regulation of pulmonary immune responses to subunit vaccines against tuberculosis. Britton, Triccas, West

NHMRC Project Grant (2010-2012). Visualisation of gamma-delta T cell responses in cutaneous inflammation. Weninger, Triccas

ARC Discovery Project (2010-2012). Bacterial filamentation as a survival strategy: a goldmine for the discovery of new cell division regulators. Harry, Thomas, Triccas, Britton

Rebecca L Cooper Research Foundation Grant (2010): Identifying new compounds to treat infection with the major lung pathogen Mycobacterium tuberculosis. Triccas

Selected recent publications

Nambiar, J. K., Ryan, A. A., Kong, C. U., Britton, W. J. and Triccas, J. A. (2010). of pulmonary dendritic cell function by vaccine-encoded GM-CSF enhances protective immunity against Mycobacterium tuberculosis infection. European Journal of Immunology. 40:153-161.

Ryan, A. A., Nambiar, J. K., Wozniak, T. M., Roediger, B., Shklovskaya, E., Britton, W. J., Fazekas de St Groth, B. and Triccas, J. A. (2009). Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection. Journal of Immunology. 182:7172-7.

Ng, L. G., Hsu, A., Mandell, M. A., Roediger, B., Hoeller, C., Mrass, P., Iparraguirre, A., Cavanagh, L. L., Triccas, J. A., Beverley, S. M., Scott, P. and Weninger, W. (2008). Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. Plos Pathogens. 4:e1000222.

Ryan A. A., Wozniak, T. M., Elena Shklovskaya, E., O’Donnell, M. A., Fazekas de St Groth, B., Britton, W. J. and Triccas, J. A. (2007). Improved protective efficacy against tuberculosis afforded by M. bovis BCG secreting murine GM-CSF is associated with expansion and activation of antigen presenting cells. Journal of Immunology. 179:8418-8424.
Ryan, A. A., Spratt, J. M., Britton, W. J. and Triccas, J. A. (2007). Secretion of functional monocyte chemotactic protein 3 by recombinant Mycobacterium bovis BCG attenuates vaccine virulence and maintains protective efficacy against M. tuberculosis infection. Infection and Immunity. 75:523-526.

Triccas, J. A, Shklovskaya, E., Spratt, J., Ryan, A.A., Palindera, U., Fazekas de St Groth, B and Britton, W. J. (2007). DNA- and BCG-based delivery of Flt3 ligand promotes protective immunity to Mycobacterium tuberculosis infection. Infection and Immunity. 74:5368-5375.

Wozniak, T. M., Ryan, A. A., Triccas, J. A and Britton W. J. (2006). Plasmid interleukin-23 (IL-23), but not plasmid IL-27, enhances the protective efficacy of a DNA vaccine against Mycobacterium tuberculosis infection. Infection and Immunity. 74:557-565.

Spratt, J. M., Ryan, A. A, Britton W. J. and Triccas, J. A. (2005). Epitope-Tagging Vectors for the Expression and Detection of Recombinant Proteins in Mycobacteria. Plasmid. 53 :269-273.

Sun, M, Andreassi, J. L., Lui, S, Pinto, R., Triccas, J. A. and Leyh, T. S. (2005). The trifunctional sulfate activating complex of Mycobacterium tuberculosis. Journal of Biological Chemistry. 280: 7861-7866.

Palendira, U., Spratt, J. M., Britton W. J. and Triccas, J. A. (2005). Expanding the antigenic repertoire of BCG improves protective efficacy against aerosol Mycobacterium tuberculosis infection. Vaccine. 23:1680-1685.