THE IMMUNE SYSTEM AND INFECTIONS
Mycobacterial Research Group
Centenary Institute of Cancer
Medicine & Cell Biology
Professor Warwick Britton, Dr Bernadette Saunders, Dr
James Triccas, A/Prof Helen Briscoe
The Mycobacterial Research Group studies the interaction
between the immune system and Mycobacterium
leprae, and Mycobacterium
tuberculosis, the causes of tuberculosis and leprosy, at a number of
levels. These include the cellular and
cytokine responses to infection, the genetic control of host response and the
development of new vaccines against TB. The
group includes two senior research officers, one research officer, research
assistants, PhD and honours students. It
is housed in modern laboratories in the Centenary Institute for Cancer Medicine
and Cell Biology with a dedicated PC3 facility for studies with M. tuberculosis.
Project 1: Interaction of
viral and mycobacterial infections in the lung
Tuberculosis remains a major cause of death and
morbidity throughout the world.
Protection against Mycobacterium
tuberculosis infection in the lung is dependent on the 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 types of infection in the lung is poorly understood. This interaction may influence the
effectiveness of vaccines against either mycobacterial or viral pathogens
during infection with different types of pathogen. We plan to address these questions by using
recombinant viruses which express dominant CD4 and CD8 T cell epitopes from
mycobacterial secreted proteins. Model
viruses which stimulate a limited lung infection (Influenza) and persistent
lung infection (murine gamma herpes virus) are being developed. TcR transgenic mice whose lymphocytes
recognize the dominant CD4 T cell epitope in mycobacteria are also available.
These will allow us to determine how mycobacterium-specific CD4 and CD8 memory
T cell responses, which are stimulated by short-lived or persistent viral
infections, influence T cell responses to primary infection with M. tuberculosis or the vaccine strain M. bovis (BCG). The nature of the memory responses to the
different pathogens will be examined and the effect of these responses on
protection against subsequent mycobacterial challenge. These studies are relevant to the design and
implementation of more effective vaccines against tuberculosis using
recombinant viral and mycobacterial vectors.
Research Techniques: Cellular immunology, molecular biology and
preparation of recombinant vaccine vectors, cytokine analysis, RT-PCR.
Supervisors
Prof Warwick Britton Tel: 9515 5210
Email: wbritton@med.usyd.edu.au
Dr James Triccas
Tel 9351 6182
Email: jamiet@infids.usyd.edu.au
Project 2: Making hyperactive macrophages to kill
Mycobacterium tuberculosis
Macrophages are both the host cells which are
permissive for the growth of M.
tuberculosis, and the effector cells responsible for killing these
intracellular pathogens after activation by T cells. This project will study methods for making
macrophages hyperactive in vivo to
increase their capacity to kill M. tuberculosis. Two effector molecules will be studied,
LRG47, a small GTPase stimulated by
interferon-γ, and indoleamine 2, 3 dioxygenase (IDO). Genes for these two molecules will be
expressed in lentiviral vectors to permit over-expression of the genes in
macrophages or dendritic cells and in chimeric mice. These will be studied in experimental models
of tuberculosis to determine if these overactive macrophages can kill M. tuberculosis more effectively. This
may lead to novel ways of eradicating M.
tuberculosis in patients with latent infection, and thereby increase the control
of the disease.
Research Techniques:
Molecular biology, cell biology, cellular
immunology and experimental infection.
Supervisors:
Professor Warwick Britton
Tel: 9515 5210
Email: wbritton@med.usyd.edu.au
Dr Bernadette Saunders
Tel: 9565 6114
Email: b.saunders@centenary.usyd.edu.au
Project 3: Gene expression in
leprosy infection
Leprosy is a major human infection in which the
tissue damage is caused by the host immune response to the relatively inert Mycobacterium leprae. There is a
spectrum of host responses from strong T cell reactivity in tuberculoid leprosy
to T cell anergy in lepromatous leprosy.
This project will address host responses to M. leprae in two ways:
1. Gene expression in tissues of leprosy patients
In collaboration with colleagues in Kathmandu,
we shall examine host gene expression in the skin of leprosy patients using DNA
microarray analysis. This will use skin
biopsies from patients with tuberculoid and lepromatous leprosy and patients
with leprosy reversal reaction before and after treatment for the reaction.
2. Gene response of Schwann cells and macrophages to M.
leprae
M.
leprae has the capacity to
infect Schwann cells and damage nerves, and this is responsible for the
disability in leprosy. The effects of M. leprae on Schwann cells are poorly
understood. We have access to viable M.
leprae from colleagues in the United States. The changes in cellular gene expression in Schwann
cells and macrophages will be examined using human Schwann cell macrophage cell
lines. Gene expression will be measured by microarray and RT-PCR analysis, and
the changes in selected proteins examined by immunoblotting.
Research Techniques
DNA microarrays and RT-PCR
analysis of gene expression, cellular immunology, bioinformatics.
Supervisors:
Professor Warwick Britton
Tel: 9515 5210
Email: wbritton@med.usyd.edu.au
Dr Craig Nourse
Tel: 9565 6114
Email: c.nourse@centenary.usyd.edu.au