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Michael Weekes

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 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 >900 host proteins HCMV downregulates may have antiviral function. We have applied QTV to lytic Epstein Barr Virus lytic infection, in order to identify molecules commonly targeted by multiple viruses as a measure of importance (Ersing et al. Cell Reports 2017). We have also developed approaches to determine which viral gene targets a given host factor (eLife 2017) and have applied multiplexed proteomics to subcellular fractionation (Itzhak et al. Cell Reports 2017). Most recently, a key 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 and Microbe, in press).

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 Professor Manoj Duraisingh, Harvard School of Public Health); vaccinia virus (collaboration with Professor Geoff Smith, Department of Pathology, Cambridge); Herpes Simplex and BK viruses (collaboration with Dr Colin Crump, Department of Virology, Cambridge).

 

Weekes schematic

 

Weekes lab

Key publications:

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 protein stability during cytomegalovirus infection informs on antiviral restriction. Cell Host Microbe In press.

Wang ECY, Pjechova M, Nightingale K, Vlahava V, Patel M, Ruckova E, Forbes S, Nobre L, Antrobus R, Roberts D, Fielding CA, Seirafian S, Davies J, Murrell I, Lau B, Wilkie GS, Suárez NM, Stanton RJ, Vojtesek B, Davison A, Lehner PJ, Weekes MP*, Wilkinson GWG* & Tomasec P*. Suppression of co-stimulation by human cytomegalovirus promotes evasion of cellular immune defences. Proc. Natl Acad. Sci. USA 115:4998-5003 (2018). *Joint last authors.

Gruszczyk J, Kanjee U, Chan L, Menant S, Malleret B, Lim NTY, Schmidt CQ, Mok Y, Lin KM, Pearson RD, Rangel G, Smith B, Call MJ, Weekes MP, Griffin MDW, Murphy JM, Abraham J, Sriprawat K, Menezes MJ, Ferreira MU, Russell B, Renia L, Duraisingh MT & Tham W. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science 5:48-55 (2018).

Grüringa C, Chaanda M, Lin KM, Egan E, Manzoa J, Jonese PL, Yua T, Barker Jre R, Weekes MP & Duraisingh MT. CRISPR/Cas9 knockouts reveal genetic interaction between strain-transcendent erythrocyte 5 determinants of Plasmodium falciparum invasion. Proc. Natl Acad. Sci. USA 144:E9356-E9365 (2017).

Itzhak DN, Davies C, Tyanova S, Mishra A, Williamson J, Antrobus R, Cox J, Weekes MP* & Borner GHH*. A mass spectrometry-based approach for mapping protein subcellular localization reveals the spatial proteome of mouse primary neurons. Cell Rep. 20:2706-2718 (2017). *Joint last authors.

Dankwa S, Chaand M, Kanjee U, Jiang RHY, Nobre LV, Goldberg JM, Bei AK, Moechtar MA, Grüring C, Ahouidi AD, Ndiaye D, Dieye TN, Mboup S, Weekes MP, Duraisingh MT. Genetic evidence for erythrocyte receptor glycophorin B expression levels defining a dominant plasmodium falciparum invasion pathway into human erythrocytes. Infect Immun. 85. pii: e00074-17 (2017).

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. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation. eLife Feb 10;6. pii: e22206 (2017). *Joint first 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).

 

Michael Weekes

 

 

 

 

 

 

 

 

Dr Michael Weekes

Wellcome Trust Senior Clinical Fellow

Honorary Consultant in Infectious Diseases, Addenbrooke’s Hospital

Department: Medicine

Contact: mpw1001@cam.ac.uk

01223 767811

Plain English

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.

Group members

Colin Davies · Alice Fletcher-Etherington · Kai-Min Lin · Luis Nobre · Katie Nightingale · Martin Potts · Lior Soday · Ben Ravenhill

Funding

Wellcome Trust

Medical Research Council

Evelyn Trust