Prof Mike Weekes
- Professor of Viral Immunology, Cambridge Institute for Medical Research
- I use cutting-edge proteomics to identify and characterise novel aspects of innate antiviral immunity.
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General research description:
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.
Collaborations:
At University of Cambridge
1. Professor Geoff Smith, Department of Pathology, University of Cambridge, UK: Proteomic analysis of vaccinia virus infection
2. Professor Jim Kaufman, Department of Pathology, University of Cambridge, UK: What determines the expression of individual class I MHC alleles?
3. Dr. Colin Crump, Department of Virology, University of Cambridge, UK: How do BK and Human Simplex Viruses modulate the cellular environment over time to evade immunity?
4. Dr. Mark Wills, Department of Medicine, University of Cambridge, UK: Identification of novel secreted antiviral factors released by leukocytes responding to HCMV infection
National and International
1. Dr. Richard Stanton, School of Medicine, Cardiff University, UK: How does human cytomegalovirus modulate cell surface and intracellular proteins to evade innate and adaptive immunity?
2. Professor Manoj Duraisingh, Harvard School of Public Health, USA and Professor Tandakha Dieye, Cheikh Anta Diop University, Senegal: Identification of novel receptors and therapeutic targets for malaria using quantitative multiplexed proteomics
3. Professor Matthew Freeman, Dunn School of Pathology, Oxford University, UK: Modulation of the cell surface proteome by rhomboid proteases
4. Professor Paul Digard, Roslin Institute, University of Edinburgh, UK: Identification and quantitation of novel Influenza proteins.
5. Dr. Benjamin Gewurz, Harvard Medical School, USA: How does Epstein-Barr virus evade immunity and generate malignant transformation? Can novel therapeutic targets of EBV-related cancers be identified by multiplexed proteomics?
6. Professor Andrew Davison, Glasgow University, UK: How do HCMV long non-coding RNAs modulate cellular functions?
Research
Research interests
- Host-pathogen interactions
- Malaria
Extended research description
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 ~1300 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 an 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).
