The Department of Infection and Immunity is delighted to announce that three members of staff had the privilege to present their work at the recent meeting of The Association of Physicians of Great Britain.
The Association of Physicians of Great Britain, which was founded in 1907 by Sir William Osler and others, is a respected society of eminent, mostly clinical researchers, drawn from medical schools across Britain and Ireland. Its Annual Scientific Meeting was held in the Medical School on 26 and 27 March. To present research at the meeting is considered to be a real honour and we are delighted that Dr Andrew Streets and Dr Paul Collini had their abstracts accepted for oral presentation, and Dr Roger Thompson won the poster prize. Below are further details of the work presented:
In my paper, entitled ‘Mcl-1 Regulates Mitochondrial ROS-mediated Bacterial Killing in Macrophages and Defines Susceptibility to Pulmonary Infection In COPD And HIV’ I described how we have translated basic science research, characterising a fundamental host response to pneumococcal bacteria, from in vitro and mouse models to clinic patients with chronic obstructive pulmonary disease (COPD) and HIV infection.
When the lung encounters the pneumococcus, an immune cell called the macrophage ingests and kills the bacteria before any clinical illness occurs. If this process fails, either because the cell is not functioning properly or is overwhelmed by too many bacteria, pneumonia will develop with the risk of severe complications such as blood poisoning. Our research had discovered that the macrophage is able to augment its ability to destroy bacteria that it has engulfed by employing a second wave of killing associated with its own cell death known as apoptosis associated killing. We observed that a protein called Mcl-1, which usually stabilizes the cell, is used as a switch by the macrophage to trigger this process. By developing transgenic mice that overproduce this human protein in its macrophages and comparing it with a normal mice, we were able to demonstrate that following ingestion of the bacteria the level of Mcl-1 determines the capacity to engage apoptosis-associated killing and if levels of Mcl-1 are too high the macrophages are unable to kill bacteria using mitochondrial-derived reactive oxygen species and mice are more susceptible to pneumonia. We hypothesized that people with COPD and HIV, who are many times more likely to suffer infection with the pneumococcus, might have a defect in this apoptosis associated killing process. To test this we asked volunteers with COPD or HIV to allow us to retrieve macrophages from their lungs using a flexible camera called a bronchoscope. We found that, compared with the same cells from healthy volunteers, both the COPD and HIV patients’ macrophages had increased levels of Mcl-1 and like the transgenic mice failed to appropriately engage apoptotic cell death in response to the bacteria. As a consequence they did not generate the same surge in reactive oxygen molecules and failed to kill the bacteria.
This work implies that enhanced levels of the Mcl-1 protein in macrophages in the lung of people with COPD and HIV increase susceptibility to bacterial pneumonia and modulation of this pathway may represent a new approach to preventing pneumonia.
Authors: Collini, P; Bewley, MA; Preston, JA; Budd, R; Singh, D; Shapiro, S; Whyte, MKB; Dockrell, DH
Dr Andrew Streets
Our work in the Kidney Genetics Group within the Academic Unit of Nephrology aims to develop new therapies to treat Autosomal Dominant Polycystic Kidney Disease. Recently we have shown that changes in small regulatory RNA molecules called microRNAs can lead to altered gene expression in kidney cysts. We have identified one gene which is up-regulated over 40 fold in kidney cysts. We have shown that inhibiting the function of the protein product of this gene in ADPKD cells reduces proliferation and may translate into a novel therapeutic target.