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).
Karniely S, Weekes MP, Antrobus R, Rorbach J, van Haute L, Umrania Y, Smith DL, Stanton RJ, Minczuk M, Lehner PJ & Sinclair JH. Human cytomegalovirus infection upregulates the mitochondrial transcription and translation machineries.
MBio. 7(2) pii: e00029-16. doi: 10.1128/mBio.00029-16 (2016).
Matheson NJ, Sumner J, Wals K, Rapiteanu R, Weekes MP, Vigan R, Weinelt J, Schindler M, Antrobus R, Costa ASH, Frezza C, Clish CB, Neil SJD & Lehner PJ. Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef. Cell Host Microbe 18, 409–423 (2015).
Grice GL, Lobb I, Weekes MP, Gygi SP, Antrobus R & Nathan JA. The proteasome distinguishes between heterotypic and homotypic lysine-11 linked polyubiquitin chains. Cell Reports 12, 545–553 (2015).
Egan ES, Jiang RH, Moechtar MA, Barteneva NS, Weekes MP, Nobre LV, Gygi SP, Paulo JA, Frantzreb C, Tani Y, Takahashi J, Watanabe S, Goldberg J, Paul AS, Brugnara C, Root DE, Wiegand RC, Doench JG & Duraisingh MT. A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion. Science 348, 711–714 (2015).
Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow D, Stanton RJ, Wang EC, Aicheler R, Murrell I, Wilkinson GW, Lehner PJ and 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).