skip to content

Department of Pathology

Project: Innate immune signalling, anti-viral immunity, poxviruses, vaccinology


The lab’s research projects are focused around the innate immune responses to virus infection in three main areas:

1) The innate immune response to viral nucleic acids.

Nucleic acids are powerful immunostimulatory agents. Sensing of damaged or mis-localised nucleic acids by pattern recognition receptors underlies multiple pathologies and is especially important in the context of anti-viral immunity.

Sensing of viral DNA in mammalian cells:

During DNA virus infection, the ability of our cells to sense viral genomic DNA it critical for mounting type one and type three interferon responses. Leveraging our expertise in poxvirology, a family of large DNA viruses which replicate their double stranded DNA genome in the cytoplasm, we discovered that mouse and human cells require DNA-dependent protein kinase (DNA-PK) for this process. DNA-PK binds to cytoplasmic DNA and activates the cGAS/STING pathway that drives the IRF-3 dependent production of interferons and cytokines in response to viral DNA. This pathway is required for mammalian cells to sense and respond to DNA viruses like herpesviruses and poxviruses. We also discovered that patients who have specific mutations in DNA-PKcs (the catalytic subunit of DNA-PK), can have enhanced STING signalling and IFN-I production, showing that this pathway functions in people and can lead to autoinflammatory pathology.


Sensing of viral RNA in mammalian cells:

The receptors that respond to viral RNA, such as RIG-I, MDA5 and TLR3, are equally important for triggering mammalian interferon responses to RNA virus infections. We are using our understanding of cell signalling at the molecular, biochemical and cell biological level to determine the mechanisms by with RNA sensing receptors work. For example we have defined the contribution of the linear ubiquitin chain assembly complex (LUBAC) and M1-linked ubiquitin chains to anti-viral immunity via the regulation of RNA sensing pattern recognition receptors, TLR3 and RIG-I in the context of influenza, Zika and Sendai virus infection. For example, cpdm mice, that lack SHARPIN are more susceptible to influenza infection:

We also found differing roles for SHARPIN and HOIP (the catalytic component of LUBAC) in regulation of RIG-I signalling, with HOIP and HOIL-1 being required for antiviral RIG-I signalling but SHARPIN not, despite it being recruited to the RIG-I signalling complex via NEMO:

2) Evolution of poxvirus host/pathogen interactions

In to understand how nucleic acid sensing mechanisms evolved to drive anti-viral immunity we are taking a comparative immunology approach. We are defining nucleic acid sensing mechanisms in multiple species including humans, mice and birds and, in parallel, defining how poxviruses subvert these pathways to optimise their replicative niches and driving evolution of host defence mechanisms. We have show, for example, that the cGAS/STING pathway functions in chickens and that this is subverted by Fowlpox virus, a poxvirus that infects chickens, and that the mammalian CpG DNA sensing TLR9 pathway is functionally replaced in birds by TLR21:


3) Vaccinology

There are many fundamental questions about the development of immunological memory which remain poorly understood. The initial detection of a vaccine vector by the innate immune system has long lasting consequences for the development of memory responses. We use vaccinia virus, the vaccine that was developed to eradicate smallpox to help understand these fundamental mechanisms of vaccinology. For example we have developed a panel of mutant viruses which have differential impacts on the development of lymphocyte memory. We have defined the impact of removing individual and multiple immunomodulatory proteins from vaccinia virus on vaccination responses and the generation of CD8 T cell memory

We are also working to understand the mechanisms by with vaccinia virus can generate such powerful memory immunity. We have recently discovered that vaccinia virus sabotages dendritic cell function and enters the draining lymph node to drive CD4 T cell activation, and that the pathology at the site of vaccination is almost completely dependent on opportunistic bacterial co-infection.







Key publications: 


DNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells
Dayana B Hristova, Marisa Oliveira, Emma Wagner, Alan Melcher, Kevin J Harrington, Alexandre Belot, Brian J Ferguson
iScience, in press
Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing
Rahul Singh, Yuan Wu, Alba Herrero del Valle, Kendra E Leigh, Mark TK Cheng, Brian J Ferguson, Yorgo Modis
bioRxiv, 2023.05. 25.542247
Mechanisms of type I interferon production by chicken TLR21
Rodrigo Guabiraba, Damaris Ribeiro Rodrigues, Paul T Manna, Mélanie Chollot, Vincent Saint-Martin, Sascha Trapp, Marisa Oliveira, Clare E Bryant, Brian J Ferguson
Developmental & Comparative Immunology 151, 105093
LUBAC is required for RIG-I sensing of RNA viruses
Helena C Teague, Charlotte Lefevre, Eva Rieser, Diego de Miguel, Daniel Patricio, Marisa Oliveira, Daniel S Mansur, Nerea Irigoyen, Henning Walczak, Brian J Ferguson
Cell Death & Differentiation, 1-12
Transcriptional reprogramming of natural killer cells by vaccinia virus shows both distinct and conserved features with mCMV
Delphine M Depierreux, Geoffrey L Smith, Brian J Ferguson
Frontiers in Immunology 14, e1093381
The gut microbiota and its metabolite butyrate shape metabolism and antiviral immunity along the gut-lung axis in the chicken
Rodrigo Guabiraba, Vincent Saint-Martin, Vanaique Guillory, Melanie Chollot, Isabelle Fleurot, Emmanuel Kut, Ferdinand Roesch, Ignacio Caballero, Emmanuelle Helloin, Emilie Chambellon, Brian Ferguson, Philippe Velge, Florent Kempf, Sascha Trapp
ResearchSquare Pre-print
PKR-mediated stress response enhances dengue and Zika virus replication
Taissa Ricciardi-Jorge, Edroaldo Lummertz da Rocha, Edgar Gonzalez-Kozlova, Gabriela Flavia Rodrigues-Luiz, Brian J Ferguson, Trevor Sweeney, Nerea Irigoyen, Daniel Santos Mansur
Mbio 14 (5), e00934-23
Suppression of innate immunity by the vaccinia virus protein N1 promotes skin microbiota expansion and increased immune infiltration following vaccination
Evgeniya Shmeleva, Daneil Syafiq, Anna ​Moldoveanu, Brian J Ferguson, Geoffrey L Smith
Journal of General Virology 103 (11)
DNA-PKcs restricts Zika virus spreading and is required for effective antiviral response
Daniel de Oliveira Patricio, Greicy Brisa Malaquias Dias, Lucilene Wildner Granella, Ben Trigg, Helena Claire Teague, Dina Bittencourt, André Báfica, Alfeu Zanotto-Filho, Brian Ferguson, Daniel Santos Mansur
Frontiers in Immunology 13, 1042463
Smallpox vaccination induces a substantial increase in commensal skin bacteria that promote pathology and enhance immunity
Evgeniya V Shmeleva, Mercedes Gomez de Agüero, Josef Wagner, Anton J Enright, Andrew J Macpherson, Brian J Ferguson, Geoffrey L Smith
PLoS pathogens 18 (4), e1009854
Selective modulation of cell surface proteins during vaccinia infection: A resource for identifying viral immune evasion strategies
Delphine M Depierreux, Arwen F Altenburg, Lior Soday, Alice Fletcher-Etherington, Robin Antrobus, Brian J Ferguson, Michael P Weekes, Geoffrey L Smith
PLoS Pathogens 18 (6), e1010612
Chicken cGAS senses fowlpox virus infection and regulates macrophage effector functions
Marisa Oliveira, Damaris Ribeiro Rodrigues, Vanaique Guillory, Emmanuel Kut, Efstathios S Giotis, Michael A Skinner, Rodrigo Guabiraba, Clare E Bryant, Brian J Ferguson
Frontiers in Immunology 11, 3716
Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to the Draining Lymph Node
Juliana Bernardi Aggio, Veronika Krmeská, Brian J Ferguson, Pryscilla Fanini Wowk, Antonio Gigliotti Rothfuchs
The Journal of Immunology 206 (4), 776-784
Exploiting Connections for Viral Replication
Louise H Wong, James R Edgar, Andrea Martello, Brian J Ferguson, Emily R Eden
Frontiers in Cell and Developmental Biology 9, 284
Viral interactions with non-homologous end-joining: a game of hide-and-seek
Dayana B Hristova, Katharina B Lauer, Brian J Ferguson
The Journal of General Virology 101 (11), 1133
ISG15-Induced IL-10 Is a Novel Anti-Inflammatory Myeloid Axis Disrupted during Active Tuberculosis
Paula Fernandes dos Santos, Johan Van Weyenbergh, Murilo Delgobo, Daniel de Oliveira Patricio, Brian J. Ferguson, Rodrigo Guabiraba, Tim Dierckx, Soraya Maria Menezes, André Báfica and Daniel Santos Mansur
Journal of Immunology, Volume 200(2)
The Non-Homologous End Joining Protein PAXX Acts to Restrict HSV-1 Infection
Ben J. Trigg, Katharina B. Lauer, Paula Fernandes dos Santos, Heather Coleman, Gabriel Balmus, Daniel S. Mansur and Brian J. Ferguson
Viruses, Volume 9(11)
Genome-wide analyses reveal a highly conserved Dengue virus envelope peptide which is critical for virus viability and antigenic in humans
RC Fleith, FP Lobo, PF dos Santos, MM Rocha, J Bordignon, DM Strottmann, DO Patricio, WR Pavanelli, M Lo Sarzi, CN Dos Santos, BJ Ferguson, DS Mansur
Scientific Reports 6, Article number: 36339
LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation
J Zinngrebe, E Rieser, L Taraborrelli, N Peltzer, T Hartwig, H Ren, I Kovács, C Endres, P Draber, M Darding, S von Karstedt, J Lemke, B Dome, M Bergmann , BJ Ferguson*, H Walczak*
J Experimental Medicine (In Press)
Increased attenuation but decreased immunogenicity by deletion of multiple vaccinia virus immunomodulators
RP Sumner, H Ren, BJ Ferguson, GL Smith
Vaccine Volume 34, Pages 4827–4834
The Schistosoma mansoni T2 ribonuclease omega-1 modulates inflammasome-dependent IL-1beta secretion in macrophages
BJ Ferguson, S Newland, SE Gibbs, P Tourlomousis, P Fernandes dos Santos, MN Patel, SW Hall, H Walczak, G Schramm, H Haas, DW Dunne, A Cooke, and P Zaccone
International Journal for Parasitology Volume 45, Issue 13 Pages 809–813
Functions of DNA damage machinery in the innate immune response to DNA virus infection
BJ Trigg and BJ Ferguson
Current Opinion in Virology Volume 15, Pages 56–62
International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease
CE Bryant, S Orr, BJ Ferguson, MF Symmons, JP Boyle, and TP Monie
Pharmacological Reviews vol. 67 no. 2 462-504
Enhancement of CD8+ T‐cell memory by removal of a vaccinia virus NF‐κB inhibitor
H Ren, BJ Ferguson, C Maluquer de Motes, RP Sumner, L Harman, GL Smith
Immunology 145 (1), 34-49
The role of shed placental DNA in the systemic inflammatory syndrome of pre-eclampsia
JDR Hartley, BJ Ferguson, A Moffett
American Journal of Obstetrics and Gynecology Volume 213, Issue 3, Pages 268–277
Intracellular sensing of viral DNA by the innate immune system
DS Mansur, GL Smith, BJ Ferguson 
Microbes and Infection 16 (12), 1002-1012
Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
CH Ku, BJ Ferguson J Vis Expts e51593-e51593
A mechanism for the inhibition of DNA-PK mediated DNA sensing by a virus
NE Peters, BJ Ferguson, M Mazzon, AS Fahy, E Krystofinska, R Arribas-Bosacoma, LH Pearl, H Ren, GL Smith
PloS Pathogens 9(10): e1003649
Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity
GL Smith, CTO Benfield, CM de Motes, M Mazzon, SWJ Ember, BJ Ferguson, RP Sumner
Journal of General Virology, 94: 2367-2392
A mechanism for induction of a hypoxic response by vaccinia virus
M Mazzon, NE Peters, C Loenarz, EM Krysztofinska, SWJ Ember, BJ Ferguson, GL Smith
Proceedings of the National Academy of Sciences, 110 (30), 12444-12449
Vaccinia virus protein N2 is a nuclear IRF3 inhibitor that promotes virulence
BJ Ferguson, CTO Benfield, H Ren, VH Lee, GL Frazer, P Strnadova, RP Sumner, GL Smith
Journal of General Virology, 94 (9), 2070-2081
Poxvirus Targeting of E3 Ligase β-TrCP by Molecular Mimicry: A Mechanism to Inhibit NF-κB Activation and Promote Immune Evasion and Virulence
DS Mansur, CM de Motes, L Unterholzner, RP Sumner, BJ Ferguson, H Ren, P Strnadova, AG Bowie, GL Smith
PLoS pathogens 9 (2), e1003183
Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
SWJ Ember, H Ren, BJ Ferguson, GL Smith
Journal of General Virology 93 (Pt 10), 2098-2108
DNA-PK is a DNA sensor for IRF-3-dependent innate immunity
BJ Ferguson, DS Mansur, NE Peters, H Ren, GL Smith
eLife Sciences 1 e00047


Associate Professor in Innate Immunity
SBS Infection and Immunity Theme Lead

Contact Details

Department of Pathology
University of Cambridge
Tennis Court Road
+44 (0)1223 333730 / 33352
Takes PhD students
Available for consultancy