Role of P2X7 in innate and adaptive immunity to mycobacterial infections

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/352330

Funding Status
Closed

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Funded Activity Summary

Tuberculosis remains an enormous global health problem. Some 32% of the world s population are infected, with over 2 million persons dying each year. It is not well understood why some infected individuals develop clinical disease yet others remain healthy, but many cases are due to reactivation of dormant organisms lying within a specialized white cell, the macrophage. We know that declining socio-economic conditions, HIV co-infection, and some genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully account for the risk of an infected individual developing disease. We have recently shown that the tuberculosis bacteria can be killed by the addition of a natural compound, ATP, to infected macrophages. This process occurs when ATP activates the P2X7 receptor leading to mycobacterial killing. We have identified several polymorphisms (mutations) in the P2X7 receptor. In individuals with one particular polymorphism, designated A1513C, these people do not respond to ATP and do not kill tuberculosis using this pathway. TB patients who are heterozygous for the A1513C polymorphism show approximately a 50% reduction in mycobacterial killing. We have preliminary evidence that this A1513C polymorphism is expressed at an over represented frequency in TB patients we have tested, suggesting that having this polymorphism may increase your risk of developing tuberculosis. The aim of this project is two fold. One, we will investigate the functioning of this receptor, determining how the P2X7 receptor is activated and how it interacts with other molecules in the immune system to kill tuberculosis. Secondly we shall determine if polymorphisms in the P2X7 receptor are a risk factor for the development of tuberculosis and leprosy disease.

Funded Activity Details

Start Date: 01-01-2005

End Date: 01-01-2007

Funding Scheme: NHMRC Project Grants

Funding Amount: $472,500.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Infectious Diseases

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Apoptosis | Genetic risk factors | Genetic susceptibility to leprosy | Genetic susceptibility to mycobacterial infections | Host defences | Innate and adaptive immunity | Killing of intracellular pathogens | P2X7 receptors | Regulation of pro-inflammatory cytokines | Tuberculosis and Leprosy

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