December 2014 Lab of the Month - Amy Buck
Our featured lab in December 2014 is that of Amy Buck in the Centre for Immunity, Infection and Evolution at Kings Buildings.
Research in Amy's group is focused on understanding the function and mechanism of small RNAs in host-pathogen systems, with a particular interest in small RNA turnover and trafficking.
Amy herself came to Edinburgh in 2007 to work as postdoc with Peter Ghazal in the Division of Infection and Pathway Medicine, after completing her PhD at the University of Colorado in Boulder. In 2007 she was awarded an incoming Marie Curie fellowship, and in 2009 she received a BBSRC New Investigator award and an Advanced Fellowship in the Centre for Immunity, Infection and Evolution. Shortly afterwards moved to her own lab in the Ashworth Laboratories.
Since 2012 she has been a Wellcome Trust Career Development Fellow. This year has been one of change again for Amy when her first daughter was born in March.
microRNAs and host-pathogen interactions
Work in the lab has largely focused on one specific class of small RNAs, microRNAs, which are ~22 nt RNA molecules that regulate gene expression by binding to specific mRNA transcripts, causing the mRNAs to be degraded or causing their translation to be repressed. The majority of human protein-coding genes are under selective pressure to maintain microRNA binding sites in their 3’UTRs and these small RNAs are therefore a ubiquitous and integral component of signaling pathways. Some viruses can produce their own microRNAs and also use or inhibit cellular microRNAs during their life cycles. The lab has a long-standing interest in understanding these viral-host interactions with the eventual goal of using microRNAs to improve and supplement existing therapeutic strategies. Right: Mir27 microRNA from cytomegalovirus (stained in green) in infected 3T3 cells.
Developing host-targeted microRNAs as an antiviral strategy
Amy is now working with collaborators Bernadette Dutia and Gerry McLachlan at the Roslin Institute, and Jürgen Schwarze at the Centre for Inflammation Research at Little France, to study this in more depth. The team received funding from Scottish Enterprise to study host-targeted microRNA manipulation as a potential therapy. They are testing the antiviral properties of microRNAs against influenza virus and respiratory syncytial virus, and developing methods of microRNA delivery to the lung with a view to moving a possible treatment into pre-clinical trials.
Extracellular RNAs in helminth infection
Amy’s lab is also particuarly interested in extracellular RNA, including microRNAs and other small RNAs. This was initiated by her finding that parasitic helminths secrete RNAs and these can be found in host fluids, such as serum, and her fruitful collaboaration with Rick Maizels that lead to the discovery that exosomes and RNAs are secreted by the gastrointestinal nematode Heligmosomoides polygyrus. These results suggest that small RNAs are another axis of host-parasite interactions with exciting implications for diagnostic and therapeutic applications.
Left: Electron micrographg of the helminth Heligmosomoides polygyrus studied in the lab; middle: electron micrograph of secretions from gut wall of H. polygyrus; right: electron micrograph of purified vesicles.
The lab is currently investigating the mechanisms by which the small RNAs are exported and imported into cells, and the RNA-protein (RNP) complexes that are involved in these processes. In a recent paper published in Nature Communications they showned that nematodes secrete vesicles containing microRNAs into the cells of the infected host, leading to suppression of the host immune system.
These results could inform new strategies for treating diseases caused by parasitic worms. They may also offer a possible way to treat allergies, such as hayfever, because the immune mechanism that parasites block is also linked to allergic reactions.
We can see for the first time that nematode parasites can use packages to sneak their material into the cells of other organisms. We now can develop ways to target this with implications for the billions of people and animals at risk of infectious diseases and allergy.
Members of the lab and collaborators
The lab is home to a several highly talented postdocs, research associates and PhD students. More details about each of them can be found on the newly updated Buck Lab website.
Back row: Juan Quintana (PhD student); Kashyap Chhatbar (bioinformatician); Divya Malik (PhD student) Marissa Lear (research associate); Fernando Leal (visiting scientist); Diwakar Kumar (PhD student)
Front row: Fabio Simbari (postdoc); Katrina Gordon (postdoc); Amy Buck; Jana McCaskill (postdoc)
Not shown: Gillian Coakley and Pairoa Praihirunkit (PhD students)
The Buck lab also collaborates widely with other colleagues across Edinburgh, including Rick Maizels, Judi Allen and Mark Blaxter in the Centre for Immunity, Infection and Evolution, Finn Grey and Pip Beard at the Roslin Institute, and David Tollervey in the Wellcome Trust Centre for Cell Biology at the University of Edinburgh and Jack Satsangi at the School of Molecular, Genetic and Population Health Sciences. The lab is also part of an international consortium to develop diagnostics of Riverblindness (using our expertise in extracellular small RNAs), this involves collaborators at the University of Liverpool, Leiden University and Bonn University through which funding is administered from the Bill & Melinda Gates foundation.
Read more about the work of the lab in some of their recent publications
Buck AH, Coakley G, Simbari F, Kumar S, Le Bihan T, Abreu-Goodger C, Lear M, Harcus Y, Ceroni A, Blaxter M, Ivens A and Maizels RM. Exosomes secreted by a nematode parasite transfer small RNAs to mammalian cells and regulate genes of the innate immune system” Nature Communications DOI:10.1038/ncomm6488. Read the paper.
Hoy A, Lundie R, Ivens A, Quintana J, Nausch N, Forster T, Jones F, Kabatereine K, Dunne DW, Mutapi F, MacDonald AS and Buck AH (2014) “Parasite-derived microRNAs in host serum as a novel biomarkers of helminth infection” PLOS NTDS DOI:10.1371/journal.pntd.0002701. Read the paper.
Hoy AK and Buck AH. Extracellular small RNAs: what, where, why? 2012 Biochem Soc Trans. 40(4): 886-90. Read the paper.
Libri V, Helwak A, Miesen P, Santhakumar D, Borger JG, Kudla G, Grey F, Tollervey D, Buck AH. Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target. 2011 PNAS 10.1073/pnas.1114204109. Read the paper.
Santhakumar D, Forster T, Laqtom N, Fragkoudis F, Dickinson P, Abreu-Goodger C, Manakov SA, Roy Choudhury N, Griffiths SJ, Vermeulen A, Enright AJ, Dutia, B, Kohl A, Ghazal P and Buck AH. Combined agonist-antagonist genome-wide functional screening identifies broadly active antiviral microRNAs. 2010 PNAS 107, 13830-13835. Read the paper.
Buck AH, Santoyo-Lopez J, Robertson KA, Kumar DS, Reczko M and Ghazal P. Discrete clusters of virus-encoded micrornas are associated with complementary strands of the genome and the 7.2-kilobase stable intron in murine cytomegalovirus. 2007 J Virol 81(24): 13761-13770. Read the paper.
- New paper shows how parasites use subterfuge to manipulate immune system
- Story featuring Amy's research on University website
- Science Daily feature on Amy's work
- Buck lab receives Proof of Concept grant from Scottish Enterprise
- Buck lab website
- Centre for Immunity, Infection and Evolution
- Institute of Immunology and Infection Research
- School of Biological Sciences, University of Edinburgh
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