Defining the human host response for better TB treatment

Lead Researcher:

Prof Joseph Keane

Award Date:

1 January 2012

Host Institution:

St James’ Hospital

Scheme:

Clinician Scientist Award

Summary:

TB is a major global public health emergency, and in Ireland the epidemic is getting more complex with the emergence of multiple-drug-resistant tuberculosis (MDR). Our HRB-funded TB research group at St James’s and Trinity are dedicated to improving Ireland’s response to the epidemic; through better health policies, TB education, as well as improving our understanding of the scientific basis of this dreaded disease. This grant seeks to improve our understanding of how the bodies’ immune system deals with infection by the bacteria that causes tuberculosis. Using material from patients, and bacteria from infected persons, we can figure out the ways that human immunity is corrupted by this invading parasite. Specifically, we will examine how normally helpful T-cells are interfered with by TB-infected lung macrophages. We have also assembled a team of researchers that are expert at understanding how the genes of immunity can be subverted by the bacteria. If we can appreciate this process better, we can invent new treatments and vaccines that will support the infected patient. The group at St James’s have an outstanding opportunity to work with TB patients and the national TB microbiology laboratory, to sort out these pathways of immune protection. Advances in this field will lead to therapies that can take on resistant infections, and better address the Irish epidemic; that is clearly not in control.

Abstract: Only 10% of people infected with Mycobacterium tuberculosis (Mtb) go on to develop the disease, but the growing global epidemic and the development of multiple drug resistant (MDR) tuberculosis clearly demonstrate that the pathogen is still a global health emergency. One of the main biological factors that explain the success of this bacillus, is its ability to parasitise the human host - through mechanisms that suppress the normal human immune response. We and others have described how the human alveolar macrophage is subverted after infection by Mtb. We have new data suggesting that infected macrophages drive T-regulatory responses in the lung, and are toxic to helpful CD4 and CD8 T-cells. Others have suggested that the bacillus also manipulates microRNA, which is a key regulator of innate and adaptive immunity. In this renewal of our CSA award, it is proposed to model host immunity using clinical isolates of Mtb and human alveolar macrophages from normal and susceptible hosts (smokers). The immunosuppressive phenotypes mentioned will be studied and drugged to see if we can tip the balance in favour of the host and towards the elimination of this important pathogen. Improving our understanding of the immune biology of this disease should uncover therapeutic targets that might be exploited through immunotherapy as well as better vaccine design.