Defining the effects of transplant immunosuppressants on innate immunity to fungi

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Organ transplantation is an increasingly common treatment for a range of diseases, but requires that individuals take life-long immunosuppressive medication. These drugs stop the immune system rejecting the transplant, but increase susceptibility to life-threatening invasive fungal infections. These infections have a mortality in excess of 40% overall, and require a long duration of highly toxic, expensive anti-fungal therapy. Understanding the immunological mechanisms that predispose some patients to these infections is critical to improving outcome.The research is relevant to invasive fungal infection and specifically invasive aspergillosis. Invasive aspergillosis has emerged as the commonest fungal infection causing death in developed countries, with a mortality of 40% to 90%. There are estimated to be 3000 to 4000 deaths from this disease per annum in the UK. Invasive aspergillosis almost exclusively occurs in immunocompromised patients, and solid organ transplant patients have emerged as a rapidly growing at risk population.The research is trying to define the mechanisms that lead to increased risk of fungal infection in transplant patients. The main immunosuppressive drugs these patients receive are called calcineurin inhibitors which are thought to primarily suppress T cell adaptive immune responses. However recent studies have demonstrated that calcineurin inhibitors could have major effects on immune cells called phagocytes. This is because the calcineurin pathway is required for signalling through a group of phagocyte immune sensing molecules called C-type lectins. This is very important because a range of fungal pathogens are sensed through C-type lectin receptors such as Dectin-1. The research will investigate how these drugs interfere with phagocyte sensing and killing of fungal pathogens and will further define the calcineurin-dependent mechanisms that mediate killing once a fungal pathogen has been recognised. This research is important because invasive fungal infections are a major cause of mortality in an expanding group of transplant patients and within other patient groups on maintenance therapy with calcineurin inhibitor immunosuppressive drugs. Understanding the mechanisms that lead to increased susceptibility to these infections will enable us to develop new strategies to identify when patients become at risk, and how best to restore fungal immunity when it becomes critically impaired. Furthermore defining the effects of these drugs on phagocyte function may lead to further insights into transplant rejection and is likely to have wider implications for transplant immunity as well as fungal immunity.The research will be carried out by Dr Anand Shah through a Clinical Research Fellowship. Dr Shah is a junior doctor specialising in respiratory infection and transplantation at Harefield Hospital. His fellowship will be supported by Prof. Sunil Shaunak, Dr Darius Armstrong-James and Dr Elaine Bignell at Imperial College, Professor Gordon Brown at the University of Aberdeen, and Dr. Anna Reed at Harefield Hospital. Professor Shaunak is a leading Infectious Diseases Clinical Academic focussed on translational medicine development. Dr Armstrong-James is an MRC Clinician Scientist in fungal immunology who has developed a relevant transplant model of fungal infection. Professor Brown is a renowned fungal immunologist who discovered the C-type lectin fungal sensor Dectin-1. Dr. Reed is a lung transplant physician at Harefield Hospital.The research will be primarily focussed on a new calcineurin inhibitor based mouse model of invasive aspergillosis. This model will be used to define the effects of calcineurin inhibitor drugs on phagocyte killing of fungi, and how this is affected in aspergillosis. In addition, we have ethical approval to confirm the model-based findings through targeted observational studies of lung transplant patients with invasive aspergillosis at Harefield Hospital.