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(A*STAR) RNA-based sensors of host-imposed stress in the major fungal pathogen of human lungs: Potential as drug targets


Project Description

The often-fatal fungal lung disease invasive aspergillosis (IA) has claimed more than 8 million human lives since its
emergence ~ 40 years ago. IA-related mortality is unacceptably high (50- 90%) and usually results from respiratory failure due to haemorrhage occurring at sites of fungal invasion. The mechanistic basis of tissue invasion by A. fumigatus remains unknown, however our recent work on fungal gene expression during lung infection has shown that adaptation to stresses encountered within the human lung a) dominate the tissue colonisation transcriptome and b) are a necessary pre-requisite for tissue invasion as mutants which are less fit under host-imposed stresses do not colonise tissue.
RNAs are well-suited to act as cellular sensors that detect and respond to metabolite changes in the environment, due to their ability to fold into complex structures. Recently we described a genome-wide strategy called PARCEL that experimentally identifies RNA aptamers in vitro, in a high-throughput manner. By applying PARCEL to identify RNA aptamers of the A. fumigatus genome we now aim to exploit our extensive experience in host-fungal interactions, transcriptomics and pathogen functional genomics to seek the existence of potentially druggable RNA-based sensors of host-imposed stress.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

• Tapsin, S., Sun, M., Shen, Y. et al. Genome-wide identification of natural RNA aptamers in prokaryotes and eukaryotes. Nat Commun 9, 1289 (2018) doi:10.1038/s41467-018-03675-1

• Bertuzzi M., Schrettl M., Alcazar-Fuoli L., Cairns T., Muñoz A., Walker L., Herbst S., Safari M., Cheverton A., Chen D., Liu H., Saijo S., Fedorova N., Armstrong-James D., Munro C., Read N., Filler S., Espeso E., Nierman W., Haas H., Bignell E. (2014) The pH-Responsive PacC Transcription Factor of Aspergillus fumigatus Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis PLoS Pathog 10(10): e1004413.

• Christopher J. Robinson, Helen A. Vincent, Ming-Cheng Wu, Phillip T. Lowe, Mark S. Dunstan, David Leys, and Jason Micklefield (2014) Modular Riboswitch Toolsets for Synthetic Genetic Control in Diverse Bacterial Species Journal of the American Chemical Society 2014 136 (30), 10615-10624, DOI: 10.1021/ja502873j

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