Innate immune evasion by intracellular pathogens
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects 60-90% of individuals. Following primary infection, HCMV establishes a latent infection under the control of a healthy immune system. Reactivation from viral latency to productive infection causes serious disease in immunocompromised individuals, such as transplant recipients and AIDS patients.
Our aim is to understand how human cytomegalovirus and other intracellular pathogens evade innate immunity. We combine cutting-edge tandem mass tag-based multiplexed proteomics with detailed molecular studies to focus on novel cellular targets.
We recently developed ‘Quantitative Temporal Viromics’, a proteomic technique that provides a systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection. Applied to human cytomegalovirus infection, this technology provided a slew of novel data, detailing how HCMV orchestrates the expression of >8,000 cellular proteins to manipulate intrinsic, innate, and adaptive immune defences in addition to host signalling and metabolism. As well as a variety of novel innate and adaptive immune ligands, we identified viral proteins present early in infection at the cell surface, potential therapeutic targets.
Our research focuses on the following areas:
- Developing QTV to refine our insights, particularly focusing on early host targets of CMV that restrict viral infection.
- Detailed molecular studies of the function and mechanism of action of key antiviral proteins. How do CMV viral proteins target these factors for destruction?
- Application of our technology to study other intracellular pathogens for example Malaria (collaboration with Professor Manoj Duraisingh, Harvard School of Public Health), Influenza (collaboration with Professor Paul Digard, Roslin Institute) and Chlamydia (collaboration with Dr. Jane Goodall, University of Cambridge Department of Medicine).
Key publications:
Ersing I, Nobre L, Wang LW, Soday L, Ma Y, Paulo JA, Narita Y, Ashbaugh CW, Jiang C, Grayson NE, Kieff E, Gygi SP, Weekes MP*, Gewurz BE*. A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells. Cell Rep. 19(7):1479-1493 (2017). *Joint last authors
Fielding CA*, Weekes MP*, Nobre LV, Ruckova E, Wilkie GS, Paulo JA, Chang C, Suárez NM, Davies JA, Antrobus R, Stanton RJ, Aicheler RJ, Nichols H, Vojtesek B, Trowsdale J, Davison AJ, Gygi SP, Tomasec P, Lehner PJ, Wilkinson GW. *Joint first authors Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation. eLife Feb 10;6. pii: e22206 (2017).
White RR, Ponsford AH, Weekes MP, Rodrigues RB, Ascher DB, Mol M, Selkirk ME, Gygi SP, Sanderson CM, Artavanis-Tsakonas K. Ubiquitin-Dependent Modification of Skeletal Muscle by the Parasitic Nematode, Trichinella spiralis. PLoS Pathog. 12(11):e1005977 (2016).
Hoare M, Ito Y, Kang TW, Weekes MP, Matheson NJ, Patten DA, Shetty S, Parry AJ, Menon S, Salama R, Antrobus R, Tomimatsu K, Howat W, Lehner PJ, Zender L, Narita M. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nature Cell Biol. 18(9):979-92 (2016).
Turnbull ML, Wise HM, Nicol MQ, Smith N, Dunfee RL, Beard PM, Jagger BW, Ligertwood Y, Hardisty GR, Xiao H, Benton DJ, Coburn AM, Paulo JA, Gygi SP, McCauley JW, Taubenberger JK, Lycett SJ, Weekes MP, Dutia BM, Digard P. Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity. J. Virol. 90, 9263-84 (2016).
Long J, Basu Roy R, Zhang YJ, Antrobus R, Du Y, Smith DL, Weekes MP*, Javid B*. Plasma Membrane Profiling Reveals Upregulation of ABCA1 by Infected Macrophages Leading to Restriction of Mycobacterial Growth. Front Microbiol. 7:1086. doi: 10.3389/fmicb.2016.01086 (2016). *Joint last authors
Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow D, Stanton RJ, Wang EC, Aicheler R, Murrell I, Wilkinson GW, Lehner PJ & Gygi SP. Quantitative temporal viromics: an approach to investigate host-pathogen interaction. Cell 157, 1460-1472 (2014).
Weekes MP, Tan SY, Poole E, Talbot S, Antrobus R, Smith DL, Montag C, Gygi SP, Sinclair JH & Lehner PJ. Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340, 199-202 (2013).
