Role of CFTR in bacterial clearance by macrophages
Understanding how multi-drug resistant superbug Burkholderia cepacia evades the natural defences of people with cystic fibrosis and developing a new kind of treatment to tackle it.
- B. cepacia and to develop associated drug discovery tools
- Professor Miguel Valvano leads the world-class team, building on pioneering work at the University of Western Ontario, funded by CF Canada
- The objective is to enable the development of more effective treatments for B. cepacia and other emerging CF pathogens
A key part of the Trust's research strategy is supporting research aimed at finding new ways to treat chronic infection and inflammation. In people with cystic fibrosis certain bugs are able to turn the body's immune system against itself by disrupting the normal processes for dealing with invaders and causing harmful levels of inflammation. They are also very difficult to treat because they are able to block conventional antibiotics.
What is B. cepacia?
B. cepacia is one of these dangerous bugs. It is a multi-drug-resistant bacterium that lives in damp or wet places. While it rarely causes infection in healthy people, it can be very harmful to people with cystic fibrosis. Approximately six per cent of adults with cystic fibrosis in the UK have this kind of infection and it is even more prevalent in other countries. Patients with B. cepacia have to be strictly isolated from other people with cystic fibrosis, and they are typically ineligible for lung transplant.
In healthy cells, harmful bacteria are normally engulfed and digested by special cells in the immune system called 'macrophages'. A macrophage is like a cellular version of Pac-Man, seeking out and gobbling up invaders. However, B. cepacia bacteria seem to be able to survive inside these macrophages in people with cystic fibrosis. In people who do not have cystic fibrosis, cells have a self-cleaning mechanism called 'autophagy' which gobbles up and recycles hostile, ageing or waste components inside the macrophages.
This mechanism does not work properly in people with cystic fibrosis. This is particularly significant in those with the most common mutation, F508del, because the CFTR protein is produced but it is not transported to the proper place in the cell (i.e. the cell wall). As it builds up in the wrong place in the cell, this waste protein has to be disposed of by the cell’s self-cleaning mechanism. However, there is so much waste CFTR, on top of all the normal ageing and cellular waste, that the disposal process becomes overwhelmed and the cell becomes stressed.
There is evidence that B. cepacia makes this situation much worse by blocking the cell's self-cleaning mechanism. It is this double-whammy effect that makes B. cepacia so dangerous for people with cystic fibrosis. The Pac-Man cells are already struggling to cope with an overwhelmingly large number of invaders who need to be gobbled up and then B. cepacia comes along and compounds the problem by neutralising their ability to gobble up and kill the invaders.
How will the grant be used?
With this grant, Professor Valvano aims first to develop a better understanding of how cystic fibrosis affects the normal functioning of macrophages and the precise mechanisms by which B. cepacia disrupts autophagy in people with cystic fibrosis. The second stage in the project is to develop a quick and efficient way of testing large numbers of compounds with a view to finding a drug that can effectively treat B. cepacia by boosting autophagy inside the macrophages of people with cystic fibrosis.
Professor Valvano said of his project: "We have reached a point in which it may possible to directly identify molecules that can help immune cells, especially those that engulf bacteria to deal with the intracellular B. cepacia. Our research effort will be focused on developing the appropriate assays (an easily repeatable method for testing new compounds) that will enable us to screen libraries of chemical compounds in search for molecules that can help the immune cells from CF patients to clear invading bacteria."
There is an increasing level of published research to suggest that other bacteria in the B. cepacia complex and Pseudomonas aeruginosa work in a similar way so this work may also be applicable to these harmful bacteria and the assay being developed may help other researchers find new treatments for them.
The Trust is happy to fund this project because it will not only advance our fundamental understanding in this critical area but it will also deliver an assay of general value to the CF community in terms of drug development. This is part of the Trust's broader strategy to work with world-class researchers to develop more effective ways of treating cystic fibrosis lung infections and strive for a life unlimited.
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Cystic fibrosis, or CF, affects the lungs, digestive system and other organs, and there are over 10,600 people living with it in the UK.
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