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Cambridge Immunology Network

 

Mark is a Director of Research based at the Department of Medicine and Cambridge Institute of Therapeutic Immunology & Infectious Disease, where his research group focus is understanding the immune response to and immune evasion by persistent viruses.

Biography

Mark studied Microbiology at the University of Surrey where he also carried out his PhD in Virology. Following a first postdoctoral position at the University of Southampton studying the immune response to cancer, he moved to the University of Cambridge in 1993 to the Department of Medicine. There he started his work on viral immunology, becoming a principal investigator.

Mark has an active research group of PhD students and postdocs focused on understanding the immune response to persistent viruses. His group has also worked on T cells responses to SARS-CoV-2 infections and vaccination, most recently he has been working on immune dysregulation in Long COVID. Mark is also the Department's Biological Safety Officer and chairs the University's Biological Safety sub-committee. He is an Editor Board member of the Journal of General Virology. He is a member of the Microbiology Society and the British Society of Immunology.

Research

Mark's laboratory has a long-standing interest in the generation and maintenance of Human Cytomegalovirus (HCMV) specific CD4/CD8 T-cell and natural killer cells, and the role these effector cells have in the control of HCMV during long-term latent viral carriage and reactivation. Of particular interest are the mechanisms by which latent HCMV evades the immune system and is able to undergo full lytic virus reactivation but is nevertheless prevented from causing serious disease in immunocompetent individuals. Of particular interest is the control of HCMV in immunosuppressed transplant patients where HCMV primary infection and reactivation can cause serious disease. He is ultimately interested in approaches to eliminating latent HCMV carriage in important clinical settings. Marks group is also interested in the ageing immune system and the consequences this might have on the control of persistent/latent virus infections. Mark has had collaborative projects working on HIV latency and the immune response to SARS-CoV-2 infection and vaccines as well as immune dysfunction in Long COVID. Mark is funded by grants from the Medical Research Council, Welcome Trust and an industrial collaboration with GlaxoSmithKline.

Human cytomegalovirus (HCMV) provides a paradigm for how a complex viral pathogen persists and evades immune responses. Our programme of research seeks to addressed a number of important questions concerning the immunobiology of HCMV. With a particular focus on the generation, maintenance and function of memory CD8+ T cells and the immune evasion mechanism employed by the virus to modulate Natural Killer cell function.

Our longitudinal study of primary HCMV infection has shown that T cell receptor affinity appears crucial for the selection of T cells into long-term memory from the initial highly polyclonal T cell response. This process is not stochastic, as in many murine models, and is remarkably rapid, occurring over weeks not years. Selected T cell clones are very long lived – possibly retained for life.

The CD8+ T cell response to HCMV is often dominated by a distinctive population of revertant memory T cells (CD45RA+ CD28- CD8+) which were thought to have a low replicative capacity and to be close to terminal differentiation. However, we have shown these cells utilise an alternative pathway of co-stimulation to classically defined memory T cells, via the 41BB-41BBL interaction, enabling them to proliferate and re-express important chemokine receptors and adhesion molecules which allow re-homing to lymph nodes and peripheral tissues. The high frequency of these HCMV-specific revertant memory T cells maintained in virus carriers suggests they are crucial for immune control.

HCMV evades cytotoxic T cells by down-regulating class I MHC, but then has to evade natural killer (NK) cells. We have recently described a novel MHC-like gene (UL142) unique to clinical isolates that inhibits NK cell lysis in a clonally dependant manor. We are currently defining the mechanism of action of the novel viral NK evasion gene product (UL142) by identifying its ligand and how this mediates evasion of NK cell cytotoxicity.

Publications

Key publications: 

Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid. Krishna BA, Lim EY, Metaxaki M, Jackson S, Mactavous L; NIHR BioResource; Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Sithole N, Wills MR.Sci Adv. 2024 Feb 23;10(8):eadi9379. doi: 10.1126/sciadv.adi9379. Epub 2024 Feb 21.PMID: 38381822 Free PMC article.

Atypical B cells and impaired SARS-CoV-2 neutralization following heterologous vaccination in the elderly. Ferreira IATM, Lee CYC, Foster WS, Abdullahi A, Dratva LM, Tuong ZK, Stewart BJ, Ferdinand JR, Guillaume SM, Potts MOP, Perera M, Krishna BA, Peñalver A, Cabantous M, Kemp SA, Ceron-Gutierrez L, Ebrahimi S; CITIID-NIHR BioResource COVID-19 Collaboration; Lyons P, Smith KGC, Bradley J, Collier DA, McCoy LE, van der Klaauw A, Thaventhiran JED, Farooqi IS, Teichmann SA, MacAry PA, Doffinger R, Wills MR, Linterman MA, Clatworthy MR, Gupta RK.Cell Rep. 2023 Aug 29;42(8):112991. doi: 10.1016/j.celrep.2023.112991. Epub 2023 Aug 16.PMID: 37590132 Free article.

Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity. Potts M, Fletcher-Etherington A, Nightingale K, Mescia F, Bergamaschi L, Calero-Nieto FJ, Antrobus R, Williamson J; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration; Parsons H, Huttlin EL, Kingston N, Göttgens B, Bradley JR, Lehner PJ, Matheson NJ, Smith KGC, Wills MR, Lyons PA, Weekes MP.Cell Rep. 2023 Jun 27;42(6):112613. doi: 10.1016/j.celrep.2023.112613. Epub 2023 May 29.PMID: 37302069 Free PMC article.

Cytomegalovirus and Cardiovascular Disease: A Hypothetical Role for Viral G-Protein-Coupled Receptors in Hypertension. Bomfim GF, Priviero F, Poole E, Tostes RC, Sinclair JH, Stamou D, Uline MJ, Wills MR, Webb RC.Am J Hypertens. 2023 Aug 5;36(9):471-480. doi: 10.1093/ajh/hpad045.PMID: 37148218 Free PMC article. Review.

HCMV carriage in the elderly diminishes anti-viral functionality of the adaptive immune response resulting in virus replication at peripheral sites. Davies EL, Noor M, Lim EY, Houldcroft CJ, Okecha G, Atkinson C, Reeves MB, Jackson SE, Wills MR.Front Immunol. 2022 Dec 15;13:1083230. doi: 10.3389/fimmu.2022.1083230. eCollection 2022.PMID: 36591233 Free PMC article.

IL-10-Secreting CD8+ T Cells Specific for Human Cytomegalovirus (HCMV): Generation, Maintenance and Phenotype. Jackson SE, Sedikides GX, Romashova V, Okecha G, Remmerswaal EBM, Bemelman FJ, Sinclair JH, Wills MR.Pathogens. 2022 Dec 13;11(12):1530. doi: 10.3390/pathogens11121530.PMID: 36558866 Free PMC article.

Human Cytomegalovirus Infection of Epithelial Cells Increases SARS-CoV-2 Superinfection by Upregulating the ACE2 Receptor. Perera MR, Greenwood EJD, Crozier TWM, Elder EG, Schmitt J, Crump CM, Lehner PJ, Wills MR, Sinclair JH; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research COVID BioResource Collaboration.J Infect Dis. 2023 Feb 14;227(4):543-553. doi: 10.1093/infdis/jiac452.PMID: 36408607 Free PMC article.

Reduced Incidence of Long Coronavirus Disease Referrals to the Cambridge University Teaching Hospital Long Coronavirus Disease Clinic. Krishna BA, Metaxaki M, Wills MR, Sithole N.Clin Infect Dis. 2023 Feb 18;76(4):738-740. doi: 10.1093/cid/ciac630.PMID: 35913432 Free PMC article.

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID. Krishna BA, Lim EY, Mactavous L; NIHR BioResource Team; Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Wills MR, Sithole N.EBioMedicine. 2022 Jul;81:104129. doi: 10.1016/j.ebiom.2022.104129. Epub 2022 Jun 27.PMID: 35772216 Free PMC article.

B cell receptor repertoire kinetics after SARS-CoV-2 infection and vaccination. Kotagiri P, Mescia F, Rae WM, Bergamaschi L, Tuong ZK, Turner L, Hunter K, Gerber PP, Hosmillo M; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration; Hess C, Clatworthy MR, Goodfellow IG, Matheson NJ, McKinney EF, Wills MR, Gupta RK, Bradley JR, Bashford-Rogers RJM, Lyons PA, Smith KGC.Cell Rep. 2022 Feb 15;38(7):110393. doi: 10.1016/j.celrep.2022.110393. Epub 2022 Jan 31.PMID: 35143756 Free PMC article.

Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid. Krishna BA, Lim EY, Metaxaki M, Jackson S, Mactavous L; NIHR BioResource; Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Sithole N, Wills MR.Sci Adv. 2024 Feb 23;10(8):eadi9379. doi: 10.1126/sciadv.adi9379. Epub 2024 Feb 21.PMID: 38381822 Free PMC article.

 
Other publications: 

 

 

 

Mason GM, Jackson S, Okecha G, Poole E, Sissons JG, Sinclair J, Wills MR. Human cytomegalovirus latency-associated proteins elicit immune-suppressive IL-10 producing CD4⁺ T cells. PLoS Pathog. 2013;9(10):e1003635. 

Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills MR, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J. 2012 Aug 29;31(17):3596-606. 

Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res. 2011 May;157(2):151-60. 

Bennett NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G, Eagle RA, Trowsdale J, Sissons JG, Wills MR. Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus. J Immunol. 2010 Jul 15;185(2):1093-102.