Department of Veterinary Medicine

Research in Veterinary Medicine

Research description

The Tiley group investigates strategies for inhibiting the replication of influenza virus. Current research is focussed on the development of genetically modified chickens carrying transgenes that suppress the expression of the viral polymerase (using miRNAs), divert the polymerase away from virus replication (RNA decoys) and enhancing natural antiviral gene activity in chicken cells (e.g Mx and interferon gene expression). This work is being done in collaboration with scientists at the Roslin Institute. We are also investigating the interaction of the viral polymerase with the genome RNAs to determine how this controls virus replication, transcription and packaging. In addition, we are developing high throughput screening assays to identify small molecule inhibitors of the polymerase/RNA interaction.

Main collaborators

• Dr Paul Digard, Dept Pathology, Cambridge.
• Dr Helen Sang, Roslin Institute, Edinburgh
• Georg Kochs, Freiburg.
• Dr Ian Brown, VLA Weybridge.

Key publications since 2001

• Lyall J.E., Irvine R.M., Sherman A., McKinley T.J., Nunez A., Purdie A., Outtrin L., Brown I., Rolleston-Smith G., Sang H. and Tiley L.S. 2011 Suppression of avian influenza transmission in genetically modified chickens. Science. 331:223-226. [PubMed]
• Benfield C.T.O., Lyall J and Tiley, LS. The cytoplasmic location of chicken Mx is not the determining factor for its lack of antivuiral activity. PLoS ONE 5:8: e12151. doi:10.1371/journal.pone.0012151. [PubMed]
• Mickleburgh I, Geng F and Tiley, LS. 2009. Mesoionic heterocyclic compunds as candidate messenger RNA cap analogue inhibitors of the influenza virus RNA polymerase cap binding activity. Antivir. Chem. Chemother. 19:213-218. [PubMed]
• Benfield C.T.O, Lyall J, Kochs G and Tiley, LS. 2008. Asparagine 631 variants of the Chicken Mx protein do not inhibit influenza replication in primary chicken embryo fibroblast cells or in vitro surrogate assays. J Virol. 82:7533-7539. [PubMed]
• Biswas, S., Kleymann, G., Swift, M., Tiley, LS., Lyall, J., Aguirre-Hernández, J. and Field, HJ. 2008. A single drug-resistance mutation in HSV-1 UL52 primase points to a difference between two helicase-primase inhibitors in their mode of interaction with the antiviral target. J. Antimicrobial Chemotherapy. 61:1044-1047. [PubMed]
• Hussein, IT, Miguel, RN, Tiley LS and Field, HJ. Substrate specificity and molecular modelling of the feline herpesvirus-1 thymidine kinase. 2008. Arch Virol. 157:495-505. [PubMed]
• Gog, J., Dos Santos, A.E., Dalton, R., Leclercq, I., Tiley, L.S., Elton,D., von Kirchbach, J., Naffakh, N., Escriou, N. and Digard, P. 2007. Codon conservation in the influenza A virus genome defines RNA packaging signals. Nucleic Acids Research. 35:1897-907. [PubMed]
• Dalton RM, Mullin AE, Amorim MJ, Medcalf E, Tiley LS, Digard P. 2006. Temperature sensitive influenza A virus genome replication results from low thermal stability of polymerase-cRNA complexes. Virol J. 3:58. [PubMed]
• Elton, D., Digard, P., Tiley, L. and Ortin J. 2006. Structure and Function of the Influenza Virus RNP . In Influenza Virology: Chapter 1, Current Topics Edited by: Kawaoka, Y. Horizon Scientific Press.
• Hunter CV, Tiley LS, Sang HM. 2005. Developments in transgenic technology: applications for medicine. Trends Mol Med. 11(6):293-8. [PubMed]
• Lee, M.T.M., Klumpp, K., Digard, P.G. and Tiley, L.S. 2003. Activation of influenza virus RNA polymerase by the 5' and 3' terminal duplex of genomic RNA. Nucleic Acids Research. 31:1624-1632. [PubMed]
• Tiley, L.S., King, A.M.Q. and Belsham, G.J. 2003. The foot-and-mouth disease virus cis-acting replication element (cre) can be complemented in trans within infected cells. J.Virol. 77:2243-2246. [PubMed]
• Lee, M., Bishop, K., Medcalf, L., Elton, D., Digard, P. and Tiley, L. 2002. Definition of the minimal viral components required for the initiation of unprimed synthesis by influenza virus RNA polymerase. Nucleic Acids Research. 30:429-438 [PubMed]
• Yu, K-L., Torri, A.F., Luo, G., Cianci, C., Grant-Young, K., Danetz, S., Tiley, L., Krystal, M. and Meanwell N.A. 2002. Structure-Activity Relationships for a Series of Thiobenzamide Influenza Fusion Inhibitors Derived from 1,3,3-Trimethyl-5-hydroxy-cyclohexylmethylamine. Bioorg Med Chem Lett. 12:3379-82. [PubMed]