Obtaining blood cells to study immune responses in tuberculosis.
Research type
Research Study
Full title
Obtaining blood cells to study immune responses in tuberculosis.
IRAS ID
236220
Contact name
Jon Friedland
Contact email
Sponsor organisation
St George's, University of London
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Research Summary
Tuberculosis (TB) is a disease caused by the bacterium Mycobacterium tuberculosis (Mtb) that causes approximately 1.5 million deaths each year. This occurs despite worldwide availability of effective drugs for TB. There is evidence that much of the disease and deaths from TB are caused by an immunological reaction to the bacteria that causes inflammation and tissue destruction in the patient. A greater understanding of the underlying pathophysiology of disease is needed. This will enable development of targeted therapies aimed at controlling inflammation. These may prevent this early deterioration and improve treatment outcomes for patients. There is growing evidence that an important component of tissue damage in TB is caused by the activity of different cell types including monocytes, neutrophils and platelets. Much of the knowledge in this area is based on our group’s previous work.
Our hypothesis is that innate immune responses drive a 'matrix degrading phenotype' characterised by production of enzymes called Matrix Metalloproteinases (MMPs) in response to TB. In this study we will isolate cells from blood obtained from the NHS Blood and Transplant centre. We shall use these cells for experiments involving cell culture and infection with live, virulent Mtb. We will use these cellular models to characterise the cell signalling pathways that lead to production of cytokines and enzymes including MMPs in response to TB infection.Summary of results
Tuberculosis (TB) is an infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb). Last year, over 10 million people fall ill with TB and over one million people died from TB. Mtb typically causes a chest infection and there is evidence that most of the death and disabilities associated with TB, are caused by the host immune response to the bacterium leading to inflammation and tissue destruction. Our research is focused on gaining a better understanding of the immune response to Mtb, so better drugs aimed at controlling inflammation and tissue damage can be developed to improve patient outcome.
Using immune cells isolated from anonymised human blood cones obtained from the South London Blood Transfusion Service, we have infected these cells with Mtb to model the early immune response in TB. Our research has highlighted that immune cells work together to cause inflammation and tissue damage in TB. For example, platelets, an important cell responsible for blood clotting, are able to interact with white blood cells called monocytes to enhance their inflammatory response to Mtb infection. Monocytes infected with Mtb are also able to direct neutrophils, another type of white blood cell, to release mediators that cause tissue destruction. In other research, we have also found that monocytes infected with Mtb at high temperatures to model fever, a common symptom of TB, have reduced inflammatory responses to suggest that fever may limit damage caused by the immune response in TB.
Aside from the direct effects of Mtb on immune cells, the immune response to Mtb is able to direct functional and metabolic changes in cells that line the lungs called epithelial cells and structural cells in the lung called fibroblasts. These changes contribute to inflammation and tissue destruction seen in TB disease. It was also found that drugs used to treat other chronic lung scarring diseases can reduce tissue destruction caused by fibroblasts. Overall, our results show that the immune response to Mtb involves complex interactions between both immune cells and cells found in the lung that contribute to tissue damage in TB.
REC name
West of Scotland REC 4
REC reference
17/WS/0249
Date of REC Opinion
12 Dec 2017
REC opinion
Further Information Favourable Opinion