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Cambridge Institute for Medical Research

 

Innate immune evasion by intracellular pathogens

General audience summary: 
Human cytomegalovirus (HCMV) infects up to 90% of all people. After initial infection, HCMV enters a latent state, where it is inactive and hides in white blood cells called monocytes. This helps HCMV to persist for the lifetime of the infected person. If HCMV reactivates in people with compromised immune systems such as those with AIDS, devastating disease can result. In unborn babies, HCMV is a leading cause of deafness and mental retardation.

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 and other viruses using a technique called proteomics, which allows precise measurement of changes in thousands of viral and cellular proteins. By understanding how HCMV interacts 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, Addenbrooke's Charitable Trust, NIHR Biomedical Research Centre

Research Group members:  Jonas Albarnaz, Leah Hunter, Hanqi Li, Martin Potts, Ben Ravenhill

Research

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. Congenital CMV affects 1/100 pregnancies, and is the leading viral cause of birth defects.

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 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 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 (Science 2013; Cell 2014). A key question has been how to determine which of the ~1,300 host proteins HCMV downregulates may have antiviral function. A major advance has been our development of three orthogonal screens to identify molecules not only downregulated but also proteasomally or lysosomally degraded by HCMV. These enabled us to identify the SWI/SNF ATPase helicase-like transcription factor as a key target of the HCMV protein UL145, and a novel antiviral restriction factor (Cell Host & Microbe 2018). Similar screens also enabled us to find that HCMV UL36 degrades the key terminal mediator of necroptosis MLKL, preventing cell death (PNAS 2020), and that HCMV RL1 degrades Schlafen-11, inhibiting another novel HCMV restriction factor. Applying the same approach to vaccinia virus infection in collaboration with Professor Geoff Smith, we identified histone deacetylase 5 as an antiviral factor for vaccinia and herpes simplex virus-1 (Cell Reports 2019). Most recently, we have developed systematic approaches to determine which viral gene targets a given host factor, including a HCMV interactome analysis (eLife 2017, Cell Host & Microbe 2018, eLife 2019).

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.
  • Application of our technology to study other intracellular pathogens, for example: Malaria (collaboration with Manoj Duraisingh, Harvard School of Public Health); Epstein-Barr virus (collaboration with Ben Gewurz, Harvard Medical School); vaccinia virus (collaboration with Geoff Smith, Department of Pathology, Cambridge); Herpes Simplex and BK viruses (collaboration with Colin Crump, Department of Virology, Cambridge).

Publications

Key publications: 

 

Soday L, Ravenhil BJ, Houghton J, Williamson JC, Antrobus R, Matheson NJ, Weekes MP. Comparative cell surface proteomic analysis of the primary human T cell and monocyte responses to type I interferon. 2021. Frontiers in Immunology. 12:600056.

Lin K, Nightingale K, Soday L, Antrobus R, Weekes MP. Rapid degradation pathways of host proteins during HCMV infection revealed by quantitative proteomics. 2021. Frontiers in Cellular and Infection Microbiology. 10:578259.

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.

Ravenhill BJ, Soday L, Houghton J, Antrobus R, Weekes MP. Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes. 2020. Scientific Reports. 10 (1): 4560.

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, Fielding CA, Fletcher-Etherington A, Soday L, Nichols H, Sugrue D, Wang ECY, Moreno P, Umrania Y, Antrobus R, 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.

Professor of Viral Immunology
Honorary Consultant in Infectious Diseases, Addenbrooke’s Hospital

Contact Details

mpw1001@cam.ac.uk
01223 767811
Takes PhD students
Available for consultancy