Genetic Modulation of the host response to pulmonary tuberculosis
This project will investigate alternative therapies to treat tuberculosis utilising viral vectors to overexpress immunological genes of interest to try and increase immunity to tuberculosis.
Tuberculosis (TB) is an enormous global health problem, infecting 2 billion individuals, causing over 2 million deaths per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease. In a latent infection an effective chronic host response contains dormant TB organisms inside activated macrophages. Cells are recruited to wall off infected macrophages and specific T cells continually induce the activate state with minimal tissue damage (immunopathology). Although currently available antibiotics can kill TB organisms, the treatment is prolonged, expensive, difficult to administer in poorly resourced regions and not effective against multi-drug resistant organisms. New therapies to treat both active disease and prevent reactivation in individuals who are latently infected are urgently required. This project will address this problem using a novel approach, namely gene manipulation to augment host immunity to TB and limit concurrent immunopathology. We will construct vectors to increase expression of the key immune molecules, the T lymphocyte activating cytokines IL-12 and IL-23, and the macrophage effector molecules LRG-47 and Indoleamine 2,3-Dioxygenase (IDO). These molecules are known to be involved in TB killing. We will determine if increasing their expression increases the killing capacity of TB-infected macrophages and we will examine how these molecules interact to aid clearance of the TB bacilli. This will further our understanding of the complex immune response to TB organisms and may lead to the development of novel therapies to treat TB infection and prevent reactivation of latent disease.
Techniques to be used include:
- Mouse models of infection
- Microbiological techniques with Mycobacterium tuberculosis
- Screening human DNA for the presence of single nucleotide polymorphisms to defined genes
- Large range of immunological and molecular biology techniques including, flow cytometry, cell culture, real-time PCR, ELISA, ELISpot, western blot, confocal microscopy, microbiological techniques
- This project also includes the possibility of spending time in Vietnam to collect and analyse samples.
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The opportunity ID for this research opportunity is: 106
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