Dr Daniel D Agranoff

SENIOR LECTURER/HON. CONSULTANT IN INFECTIOUS DISEASES

 

Proteomics Group

A major focus of our research is on the application of Proteomic Fingerprinting  technologies for the development of novel diagnostics in infectious diseases. Our principal areas of interest are infections with problematic existing diagnostics, including tuberculosis ( Lancet 2006 ), Human African Trypanosomiasis ( Lancet 2004 , Lancet 2004 , Trends in Parasitology 2005 ), invasive fungal infections and Chagas’ disease. The underlying concept is that infectious diseases are associated with circulating patterns of proteins that more or less uniquely define that disease state.

We use SELDI-ToF mass spectrometry to obtain proteomic profiles from  

serum, other body-fluids and cellular lysates and then apply machine-learning based pattern recognition algorithms to train classifiers to distinguish cases from controls. Through identification of the informative peaks in our proteomic ‘signature’ we hope to move from mass spectra to simple bedside tests based around more conventional dipstick-based formats. For protein/peptide identification, we use mass-spectrometry based technologies, including peptide mass fingerprinting, 2D gel electrophoresis and Liquid chromatography-electrospray ionisation-tandem mass spectrometry. This translational element will form an ever increasing part of our research program.  Together with collaborators at the National Institute of Medical Research (NIMR) we are also exploring the refinement of bioinformatics tools for feature selection and pattern recognition, with a particular focus on Support Vector Machines.

 

 

A major conceptual appeal of this approach in infectious diseases is that signatures reflecting host-pathogen interactions may allow accurate discrimination between infection and disease in clinical contexts where latent disease and colonisation currently muddy the waters.

TB proteomic fingerprinting – news and views •    When does a fingerprint constitute a diagnostic? •    New advances towards simple and reliable tests for active Tuberculosis http://www.nimr.mrc.ac.uk/news/2006/tb/ •    Lab work opens way to swifter, more accurate TB tests: study http://www.channelnewsasia.com/stories/health/view/230363/1/.html •    New and Simple Test for Active Tuberculosis Now Possible http://www.physorg.com/news77423174.html •   BBC link: http://news.bbc.co.uk/1/hi/health/5341968.stm

Ongoing projects include:

•    Application of proteomic fingerprinting to diagnosis of TB in Peru (Proteomic   fingerprinting for tuberculosis in Peru) (Wellcome Tropical Fellowship for Dr Gurj Sandhu)

•    Proteomic signatures for invasive fungal infections (in collaboration with Dr Tom Harrison, St George’s Hospital Medical School).

•    Exploratory proteomics for test-of-cure and disease staging in Chagas’   
      disease (Peru, Bolivia).

 
Pathogen-encoded cation transport mechanisms

Our second area of research interest is in dissecting the role of divalent cation transport in intra-cellular parasitism ( Mol Microbiol 1998 , Frotiers Biosci 2005 ). We are particularly interested in the contribution of pathogen-encoded orthologues of the Natural Resistance Associated Macrophage Protein (NRAMP) family to the intracellular survival of Mycobacterium tuberculosis and the opportunistic fungal pathogen, Cryptococcus neoformans. We have shown that orthologues expressed by both these pathogens (MRAMP ( J Exp Med 1999 ) and CRAMP ( Biochem J 2005 ), respectively) are proton-dependent transporters of a range of divalent cations including Mn2+, Zn2+, Fe2+,Co2+ and Ni2+. On-going work is exploring the functional significance of these transporters at the host-pathogen interface.