Host Response to TB

Project Leader: Dr Bernadette Saunders

TB disease causes damaging lung pathology and new therapies to treat the infection and moderate inflammation are urgently required. The group is investigating how protective immunity to tuberculosis is generated and maintained and genetic factors that influence this response.

We hope to uncover the new genes that regulate resistance or susceptibility to TB infection and determine: how these genes regulate these processes; how granuloma formation is established and maintained during TB infection; if by over expressing defined cytokines and macrophage effector molecules in vivo we can increase resistance to TB infection and limit damaging pathology.

Research focus

At the cellular level, we are investigating the inflammatory response generated following TB infection and the requirements for protective granuloma formation and maintenance.

The macrophage is a central cell in control of TB infection, as this is the cell within which the bacilli that cause TB reside. We are examining the factors that control macrophage activation leading to killing or containment of the mycobacteria bacilli. In particular we have examined the role of two macrophage effector molecules IDO and LRG-47 in control of mycobacterial infection. An honours student working in the laboratory, Gaya Nagalingam, demonstrated that murine macrophages infected with mycobacteria produce large amounts of LRG-47. Studies are underway to determine if over expression of this molecule influences development and maintenance of protective immunity to tuberculosis infection. These studies involve the generation of mice that over express LRG-47 or other macrophage effector molecules, to determine if natural immunity can be boosted in vivo. It is hoped that this research may lead to the discovery of alternative therapies to treat tuberculosis infection.

At a genetic level, we are determining the genetic influences that control susceptibility to TB. Over the last five years we have been investigating polymorphisms in the P2X7 gene and have identified a single nucleotide polymorphism in the P2X7R gene that confers increased susceptibility to extra-pulmonary tuberculosis. Studies examining other SNPs in the P2X7 gene and TLR1 and 2 are ongoing. In 2007, with collaborators Professor Chris Goodnow at the Australian Phenomics Facility Australian National University, Professor Richard Cornell at the Wellcome Trust in Oxford, UK and Dr Mark Lathrop in France, we were awarded a large five year grant by the Wellcome to identify new genes that influence resistance and susceptibility to TB. It is hoped that this exciting new project will uncover new factors that regulate resistance and susceptibility to TB.