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EASTBIO: How do IFITM proteins interact to inhibit influenza A virus infection?


   College of Medicine and Veterinary Medicine

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  Dr R Sloan, Prof P Digard  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Deanery of Biomedical Sciences: The overall aim of this project will be to determine how interferon induced transmembrane proteins (IFITMs) interact with each other to inhibit virus entry. Intracellular innate immune factors can directly inhibit virus infection in cells and are a core component of antiviral immunity. Their expression is linked to viral pathogenesis, pandemic spread of virus, and their study may reveal new means to inhibit virus. IFITM proteins are a family of antiviral factors that have been described to inhibit viral entry of a broad range of human and animal viruses including influenza A virus, dengue virus, and SARS-CoV-2.

IFITM proteins are often studied in isolation through overexpression or knockdown/out of individual IFITMs, such as IFITM3. Given that IFITMs typically exert their action as part of interferon responses, such approaches might obscure the potential for synergistic interactions between different IFITM proteins (e.g., IFITM1, IFITM2, IFITM3) in regards their antiviral activity. While IFITM proteins are known to physically interact, the functional consequences of this are not well understood, especially in the context of heterologous expression or interactions.

Further, IFITMs are thought to function by deforming membrane curvature and/or altering membrane fluidity to inhibit virus-cell membrane fusion through cholesterol binding. However, it is also unclear how IFITMs functionally interact with other interferon stimulated genes that also target the cell membrane and viral entry.

As such the aim of this project is to understand how IFITM proteins from human, mammals and avian species interact with each other, and other antiviral proteins, to provide synergistic inhibition of virus entry as part of the antiviral interferon response.

This project will use molecular virology, cell biology, immunology, comparative bioinformatic analysis, and imaging approaches to address this question in the context of influenza A virus infection. These data will reveal how IFITM proteins interact with each other and other antiviral factors to inhibit influenza A virus entry. The project will also reveal how variation in IFITM synergism and functionality in different host species may underpin the potential of zoonotic transmission of influenza A virus.

The student will receive training in mammalian cell culture, pseudotype assays, viral infection, Crispr/Cas9 genome editing, cloning and assembly, Western blot, qPCR, confocal microscopy, bioinformatic analysis, and statistical analysis.

 


Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0.
EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]
You should also ensure that two references have been send to [Email Address Removed] by the deadline using the EASTBIO Reference Form.

References

Lee WJ, Fu RM, Liang C, Sloan RD. IFITM proteins inhibit HIV-1 protein synthesis. Sci Rep. 2018 Sep 28;8(1):14551. doi: 10.1038/s41598-018-32785-5. PMID: 30266929; PMCID: PMC6162285.
Chmielewska AM, Gómez-Herranz M, Gach P, Nekulova M, Bagnucka MA, Lipińska AD, Rychłowski M, Hoffmann W, Król E, Vojtesek B, Sloan RD, Bieńkowska-Szewczyk K, Hupp T, Ball K. The Role of IFITM Proteins in Tick-Borne Encephalitis Virus Infection. J Virol. 2022 Jan 12;96(1):e0113021. doi: 10.1128/JVI.01130-21. Epub 2021 Oct 6. PMID: 34613785; PMCID: PMC8754218.
Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB; GenISIS Investigators; MOSAIC Investigators, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012 Mar 25;484(7395):519-23. doi: 10.1038/nature10921. PMID: 22446628; PMCID: PMC3648786.

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