Dr Andrew Sharkey

My research is focussed on various aspects of female reproductive health. These include: embryo implantation, causes and treatment of infertility and early placental development. A substantial body of evidence supports the view that sub-optimal placention early in pregnancy is associated with common diseases of pregnancy including pre-ecampsia, fetal growth restriction and miscarriage. Abnormal placentation can also have lifelong consequences on health outcomes through fetal programming. 

In collaboration with Professor Ashley Moffett in Pathology, we are working to understand how the invasion into the maternal decidua by fetal trophoblast cells of the placenta, which is a necessary part of placental development, may be affected by interactions with the mothers immune cells that they encounter there.  We focus on how receptors on maternal immune cells may recognise ligands on the invading fetal extravillous trophoblast cells (EVT). Some of these receptor/ligand interactions are mediated by members of the Killer cell Immunoglobulin-like Receptor family (KIR) which are expressed on maternal Natural Killer cells in the uterus (uNK). Some of these KIR proteins can bind HLA-C ligands on EVT. Both HLA-C and KIR are among the most variable genes in humans, so each pregnancy can comprise novel combinations of KIR and HLA-C. Genetic and functional studies suggest that KIR/HLA-C combinations that result in excessive inhibition of maternal uNK cells, are associated with increased risk of pre-eclampsia or fetal growth restriction (FGR). Other combinations of KIR/HLA-C that activate uNK cells are associated with increased birthweight.

Our aim is to understand the molecular and cellular processes underpinning these associations. Working with colleagues in the Obstetrics and Gynecology department at Cambridge, we also hope to develop methods to better predict women at risk of pre-ecalmpsia and FGR and to improve clinical management of these conditions.

My lab is based in the Department of Pathology, Cambridge and I am a member of the Loke Centre for Trophoblast Research. 

Selected recent publications

1. Huhn O, Zhao X, Esposito L, Moffett A, Colucci F, Sharkey AM.

How Do Uterine Natural Killer and Innate Lymphoid Cells Contribute to Successful Pregnancy?

Front Immunol. 2021 Jun 21;12:607669. doi: 10.3389/fimmu.2021.607669.                   

2. Huhn O, Ivarsson MA, Gardner L, Hollinshead M, Stinchcombe JC, Chen P, Shreeve N, Chazara O, Farrell LE, Theorell J, Ghadially H, Parham P, Griffiths G, Horowitz A, Moffett A, Sharkey AM*, Colucci F*. (* joint senior authors).

 Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy.

Nat Commun. (2020) 11:381. doi: 10.1038/s41467-019-14123-z.                    

3. Thomas JR, Appios A, Zhao X, Dutkiewicz R, Donde M, Lee CYC, Naidu P, Lee C, Cerveira J, Liu B, Ginhoux F, Burton G, Hamilton RS, Moffett A, Sharkey AM, McGovern N

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells.

J Exp Med. 2021 Jan 4;218(1):e20200891. doi: 10.1084/jem.20200891.                              

4. Shreeve N, Depierreux D, Hawkes D, Traherne JA, Sovio U, Huhn O, Jayaraman J, Horowitz A, Ghadially H, Perry JRB, Moffett A, Sled JG, Sharkey AM, Colucci F. 

 The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice.

Immunity. 2021 Apr 19:S1074-7613(21)00133-3. doi: 10.1016/j.immuni.2021.03.021.         

5. Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, Park JE, Stephenson E, Polański K, Goncalves A, Gardner L, Holmqvist S, Henriksson J, Zou A, Sharkey AM, Millar B, Innes B, Wood L, Wilbrey-Clark A, Payne RP, Ivarsson MA, Lisgo S, Filby A, Rowitch DH, Bulmer JN, Wright GJ, Stubbington MJT, Haniffa M*, Moffett A*, Teichmann SA*. 

 Single-cell reconstruction of the early maternal-fetal interface in humans.

Nature. 2018 Nov;563(7731):347-353. doi: 10.1038/s41586-018-0698-6.             

6. Filipovic I, Chiossone L, Vacca P, Hamilton R, Ingegnere T, Doisne J, Hawkes DA, Mingari MC, Sharkey AM, Moretta L, Colucci F.

Molecular definition of group 1 innate lymphoid cells in the mouse uterus.

Nat Commun. 2018 Oct 29;9(1):4492. doi: 10.1038/s41467-018-06918-3.           

7. Turco MY, Gardner L, Kay RG, Hamilton RS, Prater M, Hollinshead MS, McWhinnie A, Esposito L, Fernando R, Skelton H, Reimann F, Gribble FM, Sharkey A, Marsh SGE, O'Rahilly S, Hemberger M, Burton GJ, Moffett A.

Trophoblast organoids as a model for maternal-fetal interactions during human placentation.

Nature. 2018 Dec;564(7735):263-267. doi: 10.1038/s41586-018-0753-3.             

8. Huhn O, Chazara O, Ivarsson MA, Retière C, Venkatesan TC, Norman PJ, Hilton HG, Jayaraman J, Traherne JA, Trowsdale J, Ito M, Kling C, Parham P, Ghadially H, Moffett A, Sharkey AM*, Colucci F*. (* joint senior authors)

 High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia.

J Immunol. 2018 Nov 1;201(9):2593-2601. doi: 10.4049/jimmunol.1800860.