Re-engineering of fungal sulphur metabolism to limit mould viability and virulence.

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On a world-wide basis, A. fumigatus is the most prominent fungal pathogen of the human lung. In Europe, the all-cause burden of Aspergillus-related lung disease exceeds 2 million cases per annum, including up to 50,000 potentially fatal cases of invasive aspergillosis. The mortality rate associated with this disease is very high, and antifungal drugs currently in use have suboptimal efficacy and result in antifungal resistance. In order to develop more successful therapies, it is necessary to better understand why A. fumigatus is able to grow in mammalian tissues. Critical to this process is metabolic versatility and the capacity to obtain nutrients from the host.I have previously shown that regulation of sulphur (S) assimilation is essential for virulence, however the exact S-source exploited in lung tissue and the in vivo fungal sulphur-related metabolic status remain unknown. Therefore, in this project I aim to clarify these two important issues, which may derive in the identification of suitable targets for the development of novel antifungal therapy.First, I will utilize state-of-the-art gene expression analysis technology to investigate the sulphur-related metabolic status during infection. This approach has the potential to identify novel pathogenic processes which will aid the development of novel antifungal strategy. Based on my preliminary data, I will concentrate on two specific S-containing molecules which are strongly suggested to be relevant for virulence: methionine and sulphide (H2S).Methionine is an amino acid whose biosynthesis appears to be essential for A. fumigatus, in contrast to closely related fungal species but in line with other pathogenic fungal species. I will determine what aspect of the biosynthetic pathway is essential, as well as the functional relevance of this activity for fungal survival.In addition, I will look for compounds that specifically inhibit the activity of the fungal cobalamin-independent methionine synthase in vitro, and test their suitability as anti-aspergillosis drugs in animal models of disease. I will also ask whether A. fumigatus exploits H2S as sulphur source during infection. Sulphide is a gas produced in the human tissues, including the lungs, as signalling molecule. It has been described that H2S modifies proteins inside the cells, to regulate their activity. This protein alteration, termed sulfhydration, has been observed in bacteria and mammalian cells, demonstrating its conservation throughout evolution, and therefore, highlighting its importance. Nothing is known about sulfhydration in fungal species, I will therefore investigate whether this protein alteration occurs in A. fumigatus and whether it is important for the fungus to grow within the lungs.I will use the gathered results to look for correlates between fungal and/or mammalian sulphur metabolism, and risk for aspergillosis. This will be achieved by interrogation of the human and fungal genome data curated by the University of Manchester. Importantly, these analyses may underscore relevant epidemiologic information which may aid patient management.