Molecular basis of environmental sensing in fungi and protozoan parasites

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Many of the unicellular eukaryotic parasites that cause disease in humans are exquisitely adapted to navigate the complex and dynamic environments that they encounter in their hosts in order to sustain their life cycles and spread infection. For example, the human malaria parasite, Plasmodium falciparum, switches between human and mosquito hosts where it targets specific tissue niches in order to replicate and reproduce, and the pathogenic fungus, Cryptococcus neoformans invades the brain to causes fungal meningitis and encephalitis. These adaptations require the parasite to be able to sense and respond to the various chemical stimuli present in its' surroundings by, as yet, mostly unknown mechanisms. How do they achieve this and which proteins and mechanisms allow parasites to fulfil such complex infectious cycles?This project addresses this question by investigating candidate genes in parasitic protozoa and fungi that are predicted bioinformatically to encode cell-surface channels and receptors, but are currently uncharacterised. These proteins have no homologues in humans, so hold particular promise for drug development for a range of infectious diseases, including malaria, which alone kills hundreds of thousands of people yearly and for which the development of drug-resistance is an increasing concern. The recent explosion in genomic data means we can use protein sequence information to bridge studies in different organisms and ask whether the function and mechanism of action of proteins is conserved across the tree of life. The project will, therefore, have an interdisciplinary approach, using biochemical methods to investigate the structure and activity of candidate channels and receptors in vitro, and malaria and fungal model systems together with genetic and molecular technologies to explore and compare their roles throughout the parasitic lifecycles.