Research
Mannose binding lectin
Mannose-binding lectin (MBL) is an important host defence protein against many pathogens. So far, research into the effects of MBL on fungal infections has been very limited, however, recent reports indicate the need for further studies. It is suggested that a non-functional MBL genotype may mean that a patient is generally more susceptible to infection.
This project aims to compare MBL genotype to levels of MBL as measured in the serum. Patients attending the infectious diseases clinic suffering from chronic pulmonary aspergillosis (CPA) or allergic bronchopulmonary aspergillosis (ABPA) were tested. Two blood samples were collected. One specimen was sent for measurement of serum MBL concentrations, using an ELISA procedure. The other was analysed for MBL genotype, performed using the INNO-LiPA MBL2 kit. Statistical analyses were then performed to determine any link between functional and non-functional genotypes, and serum levels. Study ongoing.
Understanding resistance mechanisms in azole resistant Aspergillus fumigatus
Azoles are the mainstay of oral therapy for all forms of aspergillosis, and so widespread azole resistance would be devastating. This study is designed to investigate the frequency of azole resistance in Aspergillus fumigatus in the RMLM facility. Resistant isolates were studied to determine their susceptibility profiles (cross-resistance pattern), the mechanism of resistance, and their genetic relatedness by molecular typing.
Efficacy of posaconazole for chronic pulmonary aspergillosis
Posaconazole is the newest anti-fungal to be used in chronic pulmonary aspergillosis. It is generally used when patients have not improved with other anti-fungal drug. Posaconazole appears to be an effective treatment for CPA. Studies suggest relatively few side effects are experienced by patients taking posaconazole when compared with other anti-fungal drugs.
Identification of genetic risk factors associated with pulmonary aspergillosis
The main aim of the project is to identify novel variants in immune genes which predispose to pulmonary aspergillosis.
Several genetic components underlie allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis and invasive aspergillosis as supported by published studies which have already identified variants in immune regulatory genes to be associated with aspergillosis. These include SP-A2, IL-15, TGF-β, TLR9, TLR4 and MBL2. Variants of IL-15, TGF-β and TLR4 are associated with CPA, while variants of TLR9 are associated with ABPA. Different variants of SP-A2 are associated with ABPA or CPA. MBL is particularly important and mutations in the gene coding for it, MBL2, have been shown to be associated with CPA.
We have identified candidate genes using a bioinformatics approach looking at pathways and also reviewing published literature. In addition we are re-analysing the sequencing data to look for differences in frequencies of known variants between those with and without disease.
Peripheral neuropathy with azole treatment
One of the main treatments for Aspergillus disease is a group of antifungal medicines known as the ‘azoles’. This group includes itraconazole, voriconazole and posaconazole. As with many medications patients often experience unwanted side effects when taking these drugs. We are interested in a particular side effect known as peripheral neuropathy. This is characterised by a sensation of numbness or pins and needles, most often in the hands or feet. We are currently monitoring patients taking azole medications for signs of this condition in order to estimate its prevalence, recovery time and determine the risk factors.
A new blood test for the diagnosis of Aspergillosis
The diagnosis of Aspergillosis is based on a patient’s history of symptoms and a number of tests including x-rays, CT scans and blood tests. One of the most important blood tests detects and determines the level of antibodies to Aspergillus. This has traditionally be performed using a laboratory test know as Aspergillus preciptins. Recently a new test has been introduced to replace the precipitins test. It is called an ImmunoCAP antibody test. This test has many advantages over the precipitins test as it is quicker to perform and gives more precise, repeatable results. We are currently trying to determine if this new test is suitable for patients with Aspergillosis. We want to know if it aids diagnosis and reflects disease activity better than the preciptins test. This would allow us to confidently replace our original precipitins test.
Research grant funding to the group has been from:
The Fungal Research Trust
The US National Institute of Allergy and Infectious Diseases
The Wellcome Trust
The Moulton Charitable Trust
The Medical Research Council
NC3Rs
The Wolfson Foundation
The Chronic Granulomatous Disease Research Trust
National Institute of Health Research
The British Society for Antimicrobial Chemotherapy
The Hospital Infection Society
The US Amy Strelzer Manasevit Research Program
The European Union,
The European Science Foundation
The Home Office