Innate immune evasion by intracellular pathogens
General audience summary:
Human cytomegalovirus (HCMV) affects ~1/100 pregnancies and is the leading infectious cause of deafness and intellectual disability in children, and the most significant infectious cause of birth defects in the global North. There are only three anti-HCMV drugs; two of them have treatment-limiting side effects and all exhibit problematic drug resistance.
A global outbreak of monkeypox virus (MPXV) has caused >80,000 cases across >100 non-endemic countries since May 2022. More recently, a different strain of monkeypox has caused >19,000 cases in the Democratic Republic of Congo. This strain causes more disease and is more easily spread, although it is poorly understood why.
When a virus infects a cell, the cell fights back by producing antiviral proteins, which inhibit viral reproduction. The virus tries to destroy these proteins in order to survive. We hope to discover which are the most important antiviral proteins that inhibit HCMV, MPXV and other viruses using a technique called proteomics, which allows precise measurement of changes in thousands of viral and cellular proteins. By understanding how viruses interact with antiviral proteins, we may be able to inhibit these interactions, providing new treatments for viral infection.
Strategic CIMR theme: Intracellular Infections
Funding: Wellcome Trust, Medical Research Council, UK mpox consortium, Evelyn Trust
Research Group members: Ivy Di, Jo Kite, Hanqi Li, Yuchen Lin, Kate Morling, Silvey Wang, Theo von Wilmowski
Research
We use viruses as tools in order to make fundamental insights into innate antiviral immunity, and in order to develop novel therapeutics. We combine cutting-edge tandem mass tag-based multiplexed proteomics with detailed molecular studies to focus on novel cellular targets.
We previously developed ‘Quantitative Temporal Viromics’ (QTV), 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 detailed 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 (Science 2013; Cell 2014). A key question since has been how to determine which of the ~1,300 host proteins HCMV downregulates may have antiviral function. We addressed this by developing a method to identify molecules not only downregulated but also proteasomally or lysosomally degraded by HCMV (Cell Host & Microbe 2018). Similar screens also enabled us to find a number of other anti- or pro-viral factors (e.g. PNAS 2020, PNAS 2022, Cell Reports 2022, Cell Host & Microbe 2024). We have since applied this or similar approaches to multiple other viruses in collaboration, including Herpes Simplex virus (Cell Reports 2020), Epstein-Barr virus (Cell Reports 2017; Cell Metabolism 2019; Plos Pathogens 2019, Molecular Cell 2023), vaccinia virus (Cell Reports 2019), modified vaccinia Ankara (Nature Communications 2023), BK virus and influenza.
Recently, we have developed systematic approaches to determine which viral gene targets a given host factor, including an HCMV interactome analysis (eLife 2017, Cell Host & Microbe 2018, eLife 2019). We also addressed fundamental mechanisms of antiviral signalling using multiplexed subcellular proteomic profiling to analyse how 8,000 proteins move upon viral infection, identifying cytoplasm-to-nucleus translocation of CREB Regulated Transcription Coactivators-2/3 as a key novel mechanism employed in signalling diverse viral infections (Cell Reports 2025). CRTC2/3-mediated stimulation interleukin-11 production may stimulate lung fibrosis, of importance in severe COVID-19.
Our work on COVID-19 centred on developing a new COVID testing programme for Cambridge University Hospitals and Cambridge University (eLife 2020-2021). Using donations by volunteers testing positive from this programme, and from the hospital, we identified cell surface markers that may predict COVID-19 severity (Cell Reports 2023).
Our research currently focuses on the following areas:
Determining which proteins that are degraded by one or more viruses have antiviral function, then performing detailed molecular studies to determine the mechanism of action.
Development of innovative proteomic screens to identify new facets of innate immunity.
Development of novel therapeutics for HCMV, MPXV and other viruses.
Publications
Ravenhill BJ, Oliveira M, Wood G, … Chung B, Borner GHH, Weekes MP. Spatial proteomics identifies a novel CRTC-dependent viral sensing pathway that stimulates production of Interleukin-11. 2025. Cell Reports. 44(2):115263.
Li H, Fletcher-Etherington A, Hunter L, … Crump CM, Rubinsztein D, Stanton RJ, Weekes MP. Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification and viral assembly. 2024. Cell Host & Microbe. 32(4):466-478
Yiu SPT, Zerbe C, Vanderwall D, Huttlin EL, Weekes MP*, Gewurz BE*. An Epstein-Barr virus protein interaction map reveals NLRP3 inflammasome evasion via MAVS UFMylation. 2023. Molecular Cell. 83:2367-2386
Potts M, Fletcher-Etherington A, Nightingale K, … Smith KGC, Wills MR, Lyons PA, Weekes MP. Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity. 2023. Cell Reports. 42:112613
Albarnaz JD, Kite J, Oliveira M, Li H,…,Schmidt FI, Huttlin EL, Smith GL, Weekes MP. Quantitative proteomics defines mechanisms of antiviral defence and cell death during modified vaccinia Ankara infection. 2023. Nature Communications. 14:8134.
Nightingale K, Fielding CA, Zerbe C, Hunter L, … Davison AJ, Stanton RJ, Weekes MP. Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. 2022. PNAS. 119:e2108173119
Rivett L, Sridhar S, Sparkes D, Routledge M, Jones N, …., Matheson NJ, Wright G, Goodfellow I, Baker S, Weekes MP. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. 2020. eLife. 9:e58728.
Fletcher-Etherington A, Nobre L, Nightingale K, Antrobus R, Nichols J, Davison AJ, Stanton RJ, Weekes MP. Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor. 2020. PNAS. 117:18771-18779.
Jones NK, Rivett L, Sparkes D, Forrest S, Sridhar S, Young J, …, Wright G, Matheson NJ, Baker S, Weekes MP. Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19. 2020. eLife.
Soh TK, Davies CTR, Muenzner J, Connor V, Smith C, Bouton CR, Emmott E, Graham SC*, Weekes MP*, Crump CM*. Herpes simplex virus-1 pUL56 degrades GOPC to alter the plasma membrane proteome. 2020. Cell Reports. 33:108235.
Nobre L, Nightingale K, Ravenhill B, Antrobus R, Soday L, Nichols J, Wang ECY, Davison AJ, Wilkinson GWG, Stanton RJ, Huttlin EL, Weekes MP. Human cytomegalovirus interactome analysis identifies degradation hubs, domain associations and viral protein functions. eLife. 2019.
Soday L, Lu Y, Albarnaz JD, Antrobus R, Smith GL*, Weekes MP*. Quantitative temporal proteomic analysis of vaccinia virus infection reveals regulation of histone deacetylases by an interferon antagonist. 2019. Cell Reports. 7:1920-1933. *Joint last authorship.
Ravenhill BJ, Kanjee U, Ahouidi A, Nobre L, Williamson J, Goldberg JM, Antrobus R, Dieye T, Duraisingh MT, Weekes MP. Quantitative comparative analysis of human erythrocyte surface proteins between individuals from two genetically distinct populations. 2019. Communications Biology. 2(350):1-9.
Wang LW, Shen h, Nobre L, Ersing I, Paulo JA, Trudeau S, Sommermann T, Ma Y, Reinstadler B, Nomburg J, Cahir-McFarland E, Gygi SP, Mootha VK, Weekes MP*, Gewurz BE*. Epstein-Barr Virus Induced One-Carbon Metabolism Drives B-Cell Transformation. 2019. Cell Metabolism. 30:539-555. *Joint last authorship.
Caller LG, Davies CTR, Antrobus R, Lehner PJ, Weekes MP*, Crump CM*. Temporal proteomic analysis of BK polyomavirus infection reveals virus-induced G2 arrest and highly effective evasion of innate immune sensing. 2019. J. Virol. 93(e00595-19):1-21.
Wei Wang L, Wang Z, Ersing I, Nobre L, Trudeau S, Zhao B, Weekes MP, Gewurz BE. Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival. 2019. PLOS Pathogens. 15(e1008030):1-35.
Nightingale K, Lin KM, Ravenhill B, Ruckova E, Davies C, Nobre L, … Davison AJ, Wilkinson GWG, Stanton RJ, Tomasec P, Weekes MP. High definition analysis of host protein stability during human cytomegalovirus infection reveals antiviral factors and viral evasion mechanisms. 2018. Cell, Host & Microbe. 24:447-460.
