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1. Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner

Author

Aminu S. Jahun, Frederic Sorgeloos, Yasmin Chaudhry, Sabastine E. Arthur, Myra Hosmillo, Iliana Georgana, Rhys Izuagbe, Ian G. Goodfellow, Jahun, Aminu [0000-0002-4585-1701], and Apollo - University of Cambridge Repository

Subjects
NS4, genomic DNA, norovirus, Membrane Proteins, CP: Immunology, mitochondrial DNA, p204, Genomics, cytosolic DNA, DNA, Mitochondrial, Nucleotidyltransferases, General Biochemistry, Genetics and Molecular Biology, Immunity, Innate, DNA leakage, interferon response, CP: Molecular biology, Interferons, IFI16, VF1, STING, cGAS, Signal Transduction
Abstract

The cGAS-STING pathway is central to the interferon response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here, we show that the cGAS-STING pathway also contributes to the interferon response against noroviruses, currently the commonest causes of infectious gastroenteritis worldwide. We show a significant reduction in interferon-β induction and a corresponding increase in viral replication in norovirus-infected cells after deletion of STING, cGAS, or IFI16. Further, we find that immunostimulatory host genome-derived DNA and mitochondrial DNA accumulate in the cytosol of norovirus-infected cells. Lastly, overexpression of the viral NS4 protein is sufficient to drive the accumulation of cytosolic DNA. Together, our data find a role for cGAS, IFI16, and STING in the restriction of noroviruses and show the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus.

Published
2023

2. TRIM7 restricts Coxsackievirus and norovirus infection by detecting the C-terminal glutamine generated by 3C protease processing

Author

Jakub Luptak, Donna Mallery, Aminu S. Jahun, Anna Albecka, Dean Clift, Osaid Ather, Greg Slodkowicz, Ian Goodfellow, Leo James, Luptak, Jakub [0000-0002-9527-8755], Jahun, Aminu S [0000-0002-4585-1701], Apollo - University of Cambridge Repository, and Jahun, Aminu S. [0000-0002-4585-1701]

Subjects
coxsackievirus, SARS-CoV-2, Glutamine, Ubiquitin-Protein Ligases, Norovirus, 3C Viral Proteases, 3Cpro, restriction, 3C protease, TRIM7, norovirus, Mpro, degradation, ISG, Tripartite Motif Proteins, Viral Proteins, Infectious Diseases, Virology, Humans, Caliciviridae Infections, Enterovirus
Abstract

TRIM7 catalyses the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7’s extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The ‘helix-ΦQ’ degron motif recognised by TRIM7 is reminiscent of the N-end degron system and is found in ∼ 1% of cellular proteins. These features, together with TRIM7’s restricted tissue expression and lack of immune regulation suggest that viral restriction may not be its physiological function.

Published
2022

3. Interferon responses to norovirus infections: current and future perspectives

Author

Aminu S Jahun, Ian Goodfellow, Jahun, Aminu [0000-0002-4585-1701], Goodfellow, Ian [0000-0002-9483-510X], and Apollo - University of Cambridge Repository

Subjects
MDA5, Host response, Reviews, Biology, medicine.disease_cause, Virus Replication, Cell Line, Viral Proteins, fluids and secretions, Interferon, Virology, medicine, Effective treatment, Animals, Humans, innate immunity, Caliciviridae Infections, Immune Evasion, Norovirus, virus diseases, calicivirus, interferon, Immunity, Innate, RIG-I-like receptors, Interferons, medicine.drug
Abstract

Human noroviruses (HuNoVs) are increasingly becoming the main cause of transmissible gastroenteritis worldwide, with hundreds of thousands of deaths recorded annually. Yet, decades after their discovery, there is still no effective treatment or vaccine. Efforts aimed at developing vaccines or treatment will benefit from a greater understanding of norovirus-host interactions, including the host response to infection. In this review, we provide a concise overview of the evidence establishing the significance of type I and type III interferon (IFN) responses in the restriction of noroviruses. We also critically examine our current understanding of the molecular mechanisms of IFN induction in norovirus-infected cells, and outline the diverse strategies deployed by noroviruses to supress and/or avoid host IFN responses. It is our hope that this review will facilitate further discussion and increase interest in this area.

Published
2022
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5. Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

Author

Mohammad Raza, Alison E. Mather, Gilberto Betancor, Ian Merrick, Ben Taylor, Mathew A. Beale, Helen Ward, Samir Dervisevic, Michelle Cronin, Aaron R. Jeffries, Louise Smith, Steven Rudder, Mara K. N. Lawniczak, Sascha Ott, Ashok Dadrah, Luke Bedford, Gabrielle Vernet, Erik M. Volz, Rahul Batra, Johnny Debebe, Caoimhe McKerr, Samantha McGuigan, Oliver Megram, Katie Jones, Mailis Maes, Rebecca Dewar, Emma Swindells, Robert E. Johnson, Myra Hosmillo, Wen C Yew, Vineet Patel, Scott Aj Thurston, Matthew Bashton, Luke B Snell, Lynn Monaghan, David Buck, Gregory R Young, Garren Scott, Louis du Plessis, Sara Kumziene-Summerhayes, David M. Aanensen, Carl Jones, Nadine Holmes, Bernardo Gutierrez, Elizabeth Wastenge, Stavroula F Louka, Dennis Wang, Richard I. Gregory, M. Estée Török, Alistair C. Darby, Ulf Schaefer, Marc Niebel, David Robertson, E. Thomson, Carol Churcher, Patrick C McClure, Scott Elliott, Sarah Jeremiah, Katerina Galai, Matthew W. Loose, Megan Mayhew, Adhyana I K Mahanama, Angeliki Karamani, Naomi R Park, David J. Williams, Lance Turtle, Lucy R. Frost, Alicia Thornton, Jennifier Liddle, M Morgan, Tim Wyatt, Paul W Bird, Chloe Bishop, Esther Robinson, Alasdair MacLean, Inigo Martincorena, Bridget A. Knight, Emma Meader, Thomas R. Connor, Hermione J. Webster, Peter Muir, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Hannah E Bridgewater, David Simpson, Radoslaw Poplawski, Angus I. Best, David Baker, Laura Letchford, Cassie Breen, Yann Bourgeois, Matthew Gemmell, Nikki Smith, Alison Holmes, Iliana Georgana, Christophe Fraser, Natasha Jesudason, Johnathan M Evans, Rachael Stanley, Lesley-Anne Williams, Jessica Lynch, Hannah Lowe, Eleri Wilson-Davies, Paul A. Baker, Alex Makunin, James Bonfield, Helen Adams, Christopher Fearn, Peter J. Diggle, Harry D Wilson, Carmen F. Manso, Nichola Duckworth, D Haw, Anna L. Casey, Audrey Farbos, Sam Haldenby, Vicki Chalker, Roberto Amato, Elen De Lacy, Ben Farr, Eric Witele, Buddhini Samaraweera, G MacIntyre-Cockett, Husam Osman, Jane Greenaway, Justin O'Grady, Sally Forrest, Andrew Nelson, Monika Pusok, A Lloyd, Edward Barton, James W. Harrison, Sophie Palmer, Amanda Symmonds, James Shepherd, Nazreen F. Hadjirin, Stephen L. Michell, Mohammed O Hassan-Ibrahim, Fiona Ashcroft, Daniel Mair, Richard H. Myers, Dianne Irish-Tavares, Hannah C. Howson-Wells, Jacqui Prieto, Christine Sambles, Andrew Hesketh, Alp Aydin, Sónia Gonçalves, Tabitha Mahungu, Tanzina Haque, Nicholas Ellaby, Karen Oliver, Hannah Paul, Joanne Watts, Claire McMurray, Lisa J Levett, Darren Smith, Simon Cottrell, Joanna Warwick-Dugdale, Pinglawathee Madona, Matthew J. Dorman, Lizzie Meadows, Ali R Awan, Leanne M Kermack, Jennifer Hart, Angie Lackenby, Carol Scott, Michael Spencer Chapman, Lucille Rainbow, Kyriaki Nomikou, Julianne R Brown, Juan Ledesma, Adam P Westhorpe, Giri Shankar, Karlie Fallon, Tim J Sloan, Joanne Watkins, Robert Impey, Sue Edwards, Rebecca C H Brown, Robin J Moll, Karla Spellman, Laura Gifford, Jamie Young, Adrienn Angyal, Graham Phillip Taylor, Robin Manley, Gavin Dabrera, Michelle Wantoch, Rachel Williams, David Heyburn, Mirko Menegazzo, Derrick W. Crook, Gaia Nebbia, Rachel Nelson, Elaine O'Toole, Luke Foulser, Katherine L Harper, Fatima Downing, Hassan Hartman, Nathan Moore, Gemma L. Kay, Matthew Wyles, Thanh Le-Viet, Edith Vamos, John Sillitoe, Lesley Shirley, Nicholas J. Loman, Iona Willingham, Elihu Aranday-Cortes, Ian B Vipond, Jeremy Mirza, Alberto C Cerda, Michelle L Michelsen, Steven Riley, Alison Cox, Igor Siveroni, Nadua Bayzid, Shavanthi Rajatileka, Giselda Bucca, Benjamin J Cogger, Tim Boswell, Matthew J. Bull, Stephen Carmichael, Lisa Berry, Frances Bolt, Kylie E. C. Ainslie, Martyn Guest, Sarojini Pandey, Katherine L. Bellis, Shane A. McCarthy, Christopher Ruis, Fei Sang, David Bonsall, Danni Weldon, Alex Alderton, Lee Graham, Amy Trebes, Sally Corden, Adrian W Signell, Tanya Golubchik, Huw Gulliver, Rocio Martinez Nunez, Dinesh Aggarwal, Tanya Curran, Jonathan K. Ball, Sharif Shaaban, Paul Randell, Jillian Durham, Alec Birchley, Matilde Mori, Joana Dias, Katherine A Twohig, Grant Hall, Antony D Hale, Alan McNally, Jonathan D. Edgeworth, Safiah Afifi, Andrew Rambaut, Katherine Smollett, David N. Lee, Tamyo Mbisa, Shahjahan Miah, Steven Rushton, Grace Taylor-Joyce, Hannah M Pymont, Chloe L Fisher, Cordelia Langford, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Kathleen A. Williamson, Anna Price, Holli Carden, Khalil Abudahab, Joanne D. Stockton, Meera Unnikrishnan, Jennifer Collins, Emma Moles-Garcia, Michaela John, Christine Kitchen, Tranprit Saluja, Ian Harrison, Lily Tong, Thomas G. Thompson, Thomas Helmer, Amita Patel, Siona Silveira, Deborah Ashby, Claire M Bewshea, Anita Justice, Brendan A I Payne, Alexander J. Trotter, Nikos Manesis, Katie F. Loveson, Cristina V. Ariani, Wendy Chatterton, Robert J. Munn, Julian A. Hiscox, Robert Beer, Judith Breuer, Caroline E. Walters, Liam Crawford, Ara Darzi, Will P. M. Rowe, Cariad Evans, Matthew Parker, Tammy V Merrill, Louise Aigrain, Joshua Quick, Leigh M Jackson, Samuel M. Nicholls, Jonathan W. Moore, John A Hartley, Graham P. Taylor, Cherian Koshy, Shirelle Burton-Fanning, Sheila Waugh, Catherine Moore, Danielle C. Groves, Peijun Zhang, Sahar Eldirdiri, Derek Fairley, Tim E. A. Peto, Jack Cd Lee, Sharon Glaysher, Liam Prestwood, Hannah Dent, Anita Kenyon, Stephen P. Kidd, Nick Levene, Igor Starinskij, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Laia Fina, Angela Marchbank, Daniel Bradshaw, Marina Escalera Zamudio, Scott Goodwin, Andrew D Beggs, Seema Nickbakhsh, Trevor Robinson, Christina Atchison, David K. Jackson, Kathy Li, Rory Gunson, Sunando Roy, Graham S Cooke, Steven Liggett, Yasmin Chaudhry, Anoop Chauhan, Ben Temperton, Mariateresa de Cesare, Paul E Brown, Li Xu-McCrae, Martin P McHugh, Catherine Ludden, Wendy Smith, Danielle Leek, Divya K. Shah, Judith Heaney, Dominic P. Kwiatkowski, Kate M. Johnson, Robin Howe, Malorie Perry, Tetyana I. Vasylyeva, David F. Bibby, Haowei Wang, Steve Palmer, Nicholas W Machin, Charlotte A Williams, Bree Gatica-Wilcox, Angie Green, John A. Todd, Paul Elliott, Noel Craine, Jeffrey K. J. Cheng, Kate Templeton, Jonathan Hubb, Joshua Maksimovic, Christl A. Donnelly, Monique Andersson, Christopher Holmes, Dimitris Grammatopoulos, Christopher B. Williams, David G Partridge, Aminu S Jahun, Alexander Adams, Marius Cotic, Sarah Essex, Christopher J. Moore, Trudy Workman, Nicola Sheriff, Helen L Lowe, Ewan M. Harrison, Dorota Jamrozy, Rachel Jones, Ellen Higginson, Erwan Acheson, Christopher R. Jones, Oliver G. Pybus, Francesc Coll, Sian Morgan, Paul J. Parsons, Patawee Asamaphan, Veena Raviprakash, Andrew R. Bassett, Declan Bradley, Laura Atkinson, Anthony Underwood, Graciela Sluga, Sally Kay, Ellena Brooks, Oliver Eales, Andrew Whitwham, Surendra Parmar, Angela Cowell, Nicole Pacchiarini, Theocharis Tsoleridis, Jason Coombes, Robert Davies, Flavia Flaviani, Benita Percival, Jenna Nichols, Natasha M. Johnson, Salman Goudarzi, Hibo Asad, Amanda Bradley, Hannah Jones, Chrystala Constantinidou, Georgina M McManus, Minal Patel, Steven Leonard, Rebecca Williams Bmbs, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Amy Ash, John Danesh, Corin Yeats, Claudia Wierzbicki, Kordo Saeed, John Boyes, Michael A. Quail, Sharon J. Peacock, Nabil-Fareed Alikhan, Jon-Paul Keatley, Claudio Fronterre, Garry Scarlett, James McKenna, Thushan I de Silva, Malte L Pinckert, Kate B. Cook, Amy Gaskin, Rajiv Shah, Matthew T. G. Holden, Sophie J Prosolek, Nathaniel Storey, Ryan P George, Lindsay Coupland, Jenifer Mason, Matthew Carlile, Thomas D Stanton, Guy Mollett, Siddharth Mookerjee, Mary Ramsay, Steven Platt, Stephen W Attwood, Susanne Stonehouse, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Mark Whitehead, Catherine Bresner, Stefanie V Lensing, Louissa R Macfarlane-Smith, Colin P. Smith, Wendy Hogsden, Charlotte Nelson, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Samuel Robson, Zoltán Molnár, Emma L. Wise, Sian Ellard, Kim S Smith, Alice Broos, Manjinder Khakh, Kathryn A Jackson, Claire Cormie, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Meera Chand, Debra Padgett, Cassandra S Malone, James V. Price, Themoula Charalampous, Ronan A Lyons, Natalie Groves, Stefan Rooke, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Michelle Lister, Carlos Balcazar, Ana da Silva Filipe, Ben Warne, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Rose K Davidson, Angela Helen Beckett, Ember Hilvers, Kathryn McCluggage, Eileen Gallagher, Charlotte Beaver, Nick Cortes, Alisha Davies, Yusri Taha, Leah Ensell, Emanuela Pelosi, Elias Allara, Cressida Auckland, Eleanor Drury, Richard Eccles, Adela Alcolea-Medina, William L Hamilton, Rich Livett, Rachel Blacow, Margaret Hughes, Sarah François, Melisa Louise Fenton, Liz Ratcliffe, Verity Hill, Stephanie Hutchings, Kathryn Ann Harris, Emma Betteridge, William D. Fuller, Sophia T Girgis, Louise Berry, Gemma Clark, Nicholas M Redshaw, Richard Hopes, Leonardo de Oliveira Martins, Alexander J Keeley, Beth Blane, Wendy S. Barclay, Victoria Wright, Anita Lucaci, Luke R. Green, Fenella D. Halstead, Sarah Wyllie, Iraad F. Bronner, Áine O'Toole, Ravi Gupta, Leanne Kane, Clare M. McCann, Michael R Chapman, David W Eyre, Kelly Bicknell, Aileen G. Rowan, Sara Rey, Shazaad Ahmad, Diana Rajan, S Taylor, Sarah J. O'Brien, Alessandro M Carabelli, Amelia Joseph, Max Whiteley, Riaz Jannoo, Victoria Blakey, Martin D. Curran, David J. Studholme, Harmeet K Gill, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Julian Tang, Clare Pearson, Mark Kristiansen, Miren Iturriza-Gomara, National Institute for Health Research, and UK Research and Innovation

Subjects
Delta, Adult, Male, 2019-20 coronavirus outbreak, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Vaccine Efficacy, Biology, Young Adult, Exponential growth, Ethnicity, Prevalence, Humans, Child, Aged, Family Characteristics, Multidisciplinary, High prevalence, COVID-19 Genomics UK (COG-UK) Consortium11‡, SARS-CoV-2, Age Factors, COVID-19, Middle Aged, Virology, Hospitalization, England, Socioeconomic Factors, COVID-19 Nucleic Acid Testing, Child, Preschool, Female, Self Report
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

Published
2021

6. Design, development, and validation of a strand-specific RT-qPCR assay for GI and GII human Noroviruses

Author

Matthias Zibauer, Myra Hosmillo, Ian Goodfellow, Katja Marie Kjara König, Komal Nayak, Aminu S Jahun, and Lydia N. Drumright

Subjects
Norovirus RNA, human norovirus, viruses, Medicine (miscellaneous), Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Virus, law.invention, human intestinal organoids, law, medicine, strand-specific RT-qPCR, Viral rna, Polymerase chain reaction, viral gastroenteritis, RT-qPCR, virus diseases, RNA, calicivirus, Articles, Method Article, Virology, Reverse transcriptase, Cell culture, Norovirus, intestinal epithelial cells, HuNoV replicon
Abstract

Human noroviruses (HuNoV) are the major cause of viral gastroenteritis worldwide. Similar to other positive-sense single-stranded RNA viruses, norovirus RNA replication requires the formation of a negative strand RNA intermediate. Methods for detecting and quantifying the viral positive or negative sense RNA in infected cells and tissues can be used as important tools in dissecting virus replication. In this study, we have established a sensitive and strand-specific Taqman-based quantitative polymerase chain reaction (qPCR) assay for both genogroups GI and GII HuNoV. This assay shows good reproducibility, has a broad dynamic range and is able to detect a diverse range of isolates. We used tagged primers containing a non-viral sequence for the reverse transcription (RT) reaction and targeted this tag in the succeeding qPCR reaction to achieve strand specificity. The specificity of the assay was confirmed by the detection of specific viral RNA strands in the presence of high levels of the opposing strands, in both RT and qPCR reactions. Finally, we further validated the assay in norovirus replicon-bearing cell lines and norovirus-infected human small intestinal organoids, in the presence or absence of small-molecule inhibitors. Overall, we have established a strand-specific qPCR assay that can be used as a reliable method to understand the molecular details of the human norovirus life cycle.

Published
2021

7. Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner

Author

Yasmin Chaudhry, Sabastine E. Arthur, Iliana Georgana, Myra Hosmillo, Ian Goodfellow, Rhys Izuagbe, Aminu S Jahun, and Frédéric Sorgeloos

Subjects
Sting, Gene knockdown, Mitochondrial DNA, genomic DNA, chemistry.chemical_compound, biology, Viral replication, chemistry, RNA, RNA virus, biology.organism_classification, Molecular biology, DNA
Abstract

The cGAS-STING pathway is central to the IFN response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here we show that the cGAS-STING pathway also contributes to the IFN response against noroviruses, positive-sense single-stranded RNA viruses that are now one of the most common causes of infectious gastroenteritis world-wide. We show a significant reduction in IFN-β induction and a corresponding increase in viral replication in norovirus-infected cells following STING inhibition, knockdown or deletion. Upstream of STING, we show that cells lacking either cGAS or IFI16 also have severely impaired IFN responses. Further, we demonstrate that immunostimulatory host genome-derived DNA, and to a lesser extent mitochondrial DNA, accumulate in the cytosol of norovirus-infected cells. And lastly, overexpression of the viral NS4 protein was sufficient to drive the accumulation of cytosolic DNA. Together, our data elucidate a role for cGAS, IFI16 and STING in the restriction of noroviruses, and demonstrate for the first time the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus.HighlightscGAS, IFI16 and STING are required for a robust IFN response against norovirusesNuclear and mitochondrial DNA accumulate in the cytosols of infected cellsViral NS4 mediates accumulation of cytosolic DNA

Published
2021

8. Author response: Patterns of within-host genetic diversity in SARS-CoV-2

Author

Naomi Park, Ian Goodfellow, Iliana Georgana, Gerry Tonkin-Hill, Fahad A Khokhar, Luke W. Meredith, Michael Spencer Chapman, Andrew R. J. Lawson, Moritz Gerstung, Rachel Nelson, Cordelia Langford, Grant Hall, Sónia Gonçalves, Alex Alderton, Sarah L Caddy, Laura G Caller, Michael A. Quail, Yasmin Chaudhry, Ian Johnston, Jeffrey C. Barrett, David K. Jackson, Martin D. Curran, Surendra Parmar, M. Estée Török, Dominic P. Kwiatkowski, Stephen D. Bentley, Roberto Amato, Myra Hosmillo, William L Hamilton, Theresa Feltwell, John Sillitoe, Ewan M. Harrison, Aminu S Jahun, Stefanie V Lensing, Anna Yakovleva, Inigo Martincorena, Charlotte J. Houldcroft, Malte L Pinckert, and Cristina V. Ariani

Subjects
Genetics, Genetic diversity, Host (biology), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Biology
Published
2021

9. Author response: Superspreaders drive the largest outbreaks of hospital onset COVID-19 infections

Author

Luke W. Meredith, Tom Dymond, Sharon J. Peacock, Christopher Jr Illingworth, Matthew Routledge, Sally Forrest, Grant Hall, Daniela de Angelis, M. Estée Török, Lucy Rivett, William L Hamilton, Fahad A Khokhar, Ben Warne, Nick K Jones, Mark Ferris, Ian Goodfellow, Sushmita Sridhar, Stephen Baker, Nicholas M. Brown, Aminu S Jahun, Tom Fieldman, Chris Workman, Yasmin Chaudhry, Laura G Caller, Iliana Georgana, Theresa Feltwell, Effrossyni Gkrania-Klotsas, Martin D. Curran, Charlotte J. Houldcroft, Malte L Pinckert, Michael P. Weekes, Anna Yakovleva, Surendra Parmar, Ashley Popay, Christopher Jackson, Myra Hosmillo, Theodore Gouliouris, Dominic Sparkes, Kayleigh Grainger, and Sarah L Caddy

Subjects
Geography, Coronavirus disease 2019 (COVID-19), Environmental health, Outbreak
Published
2021

10. Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

Author

Benjamin J. Polacco, Kuei-Ho Chen, Matthew Whelan, Natalia Jura, Adolfo García-Sastre, Margaret Soucheray, Jacqueline M. Fabius, Kevan M. Shokat, Ian Goodfellow, Alicia L. Richards, Ajda Roic, Danielle L. Swaney, Myra Hosmillo, Danish Memon, Mahdad Noursadeghi, Ann-Kathrin Reuschl, Pedro Beltrao, Kirsten Obernier, Manisha Ummadi, Greg J. Towers, Kliment A. Verba, Aminu S Jahun, Nevan J. Krogan, Lorena Zuliani-Alvarez, Adrian Pelin, Jane Turner, Bhavya Harjai, Mehdi Bouhaddou, Hannes Braberg, Jyoti Batra, Lucy Thorne, Joseph Hiatt, and Clare Jolly

Subjects
Innate immune system, MRNA Sequencing, Viral replication, Downregulation and upregulation, Viral entry, Phosphoproteomics, RNA, Biology, Article, Subgenomic mRNA, Cell biology
Abstract

Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7 mutations outside Spike likely contribute to enhance transmission. Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and protein levels of Orf9b and Orf6, both known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein required for RNA sensing adaptor MAVS activation, and Orf9b binding and activity was regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding region to more effectively antagonise host innate immune responses through upregulation of specific subgenomic RNA synthesis and increased protein expression of key innate immune antagonists. We propose that more effective innate immune antagonism increases the likelihood of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.

Published
2021

11. Superspreaders drive the largest outbreaks of hospital onset COVID-19 infection

Author

Chris Illingworth, William Hamilton, Ben Warne, Matthew Routledge, Ashley Popay, christopher jackson, Tom Fieldman, Luke W. Meredith, Charlotte J. Houldcroft, Myra Hosmillo, Aminu S. Jahun, Laura G. Caller, Sarah L. Caddy, Anna Yakovleva, Grant Hall, Fahad A. Khokhar, Theresa Feltwell, Malte L. Pinckert, Iliana Georgana, Yasmin Chaudhry, Martin D. Curran, Surendra Parmar, Dominic Sparkes, Lucy Rivett, Nick K. Jones, Sushmita Sridhar, Sally Forrest, Tom Dymond, Kayleigh Grainger, Chris Workman, Effrossyni Gkrania-Klotsas, Nicholas M. Brown, Stephen Baker, Michael P. Weekes, Sharon J. Peacock, Ian Goodfellow, Theodore Gouliouris, Daniela de Angelis, and Estée Török

Abstract

SARS-CoV-2 is notable both for its rapid spread, and for the heterogeneity of its patterns of transmission, with multiple published incidences of superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer patterns of viral transmission occurring between patients and health care workers (HCWs) in the largest clusters of COVID-19 infection identified during the first wave of the epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates of individuals reporting symptoms, recorded individual locations, and viral genome sequence data, we show an uneven pattern of transmission between individuals, with patients being much more likely to be infected by other patients than by HCWs. Further, the data were consistent with a pattern of superspreading, whereby 21% of individuals caused 80% of transmission events. Our study provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission, and sheds light on the need for intensive and pervasive infection control procedures.

Published
2021

12. Author response: Genomic epidemiology of COVID-19 in care homes in the east of England

Author

Nicholas M. Brown, Aminu S Jahun, Surendra Parmar, Myra Hosmillo, Yasmin Chaudhry, Grant Hall, Ian Johnston, David K. Jackson, Gerry Tonkin-Hill, Gordon Dougan, Fahad A Khokhar, Roberto Amato, Alex Alderton, Luke W. Meredith, Anna Yakovleva, Ben Warne, Cordelia Langford, John Sillitoe, Ian Goodfellow, Theresa Feltwell, Laura G Caller, Sarah L Caddy, Martin D. Curran, M. Estée Török, Ewan M. Harrison, Sharon J. Peacock, Dinesh Aggarwal, Charlotte J. Houldcroft, Malte L Pinckert, Dominic P Kwiatowski, Sónia Gonçalves, Mathew A. Beale, Colin S Brown, Emily R Smith, Iliana Georgana, William L Hamilton, and Michael Spencer Chapman

Subjects
medicine.medical_specialty, Geography, Coronavirus disease 2019 (COVID-19), Care homes, Family medicine, Epidemiology, medicine
Published
2021

13. Patterns of within-host genetic diversity in SARS-CoV-2

Author

Dominic P. Kwiatkowski, Grant Hall, Theresa Feltwell, Cristina V. Ariani, Stephen D. Bentley, Rachel Nelson, Inigo Martincorena, Iliana Georgana, Fahad A Khokhar, Michael Spencer Chapman, Andrew R. J. Lawson, Sónia Gonçalves, Gerry Tonkin-Hill, Ewan Harrison, M. Estée Török, Laura G Caller, Luke W. Meredith, Stefanie V Lensing, Surendra Parmar, Naomi R Park, William L Hamilton, Alex Alderton, Moritz Gerstung, David K. Jackson, Myra Hosmillo, Anna Yakovleva, Michael A. Quail, Sarah L Caddy, Charlotte J. Houldcroft, Yasmin Chaudhry, Ian Johnston, Jeffrey C. Barrett, Malte L Pinckert, Aminu S Jahun, Roberto Amato, Ian Goodfellow, John Sillitoe, Martin D. Curran, and Cordelia Langford

Subjects
Negative selection, Mutation rate, Genetic diversity, Lineage (genetic), Phylogenetic tree, Evolutionary biology, Nonsense mutation, Biology, Allele frequency, Genome
Abstract

Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe the patterns of within-host diversity in 1,181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95% of samples show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within and between host diversity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most samples result from infection by a single lineage, we identify multiple putative examples of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between samples could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses.

Published
2020

14. Applying prospective genomic surveillance to support investigation of hospital-onset COVID-19

Author

Elinor Moore, Joanna Pocock, Ian Goodfellow, Christopher Jackson, Myra Hosmillo, M. Estée Török, Iliana Georgana, Tom Fieldman, Pooja Ravji, Christine Moody, Rachel Bousfield, James Whitehorn, Christopher J. R. Illingworth, Isobel Ramsay, Mark Ferris, Suny Coscione, Beth Blane, Matthew Routledge, Katherine Sharrocks, Yasmin Chaudhry, Ben Warne, Lucy Rivett, Rachel Tsui, Clare Leong, Daniela De Angelis, Chris Workman, Liam Brennan, David A Enoch, Malte L Pinckert, Michael P. Weekes, Nick K Jones, Aminu S Jahun, William L Hamilton, Martin D. Curran, Richard J.H. Smith, Surendra Parmar, Rhys Izuagbe, Theodore Gouliouris, Dominic Sparkes, Michelle S. Toleman, Sharon J. Peacock, Chloe E. Myers, and Helen Payne

Subjects
2019-20 coronavirus outbreak, Infectious Diseases, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Correspondence, MEDLINE, Medicine, Genomics, business, Virology
Published
2021

15. Rapid implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study

Author

Sally Forrest, Charlotte J. Houldcroft, Ashley Popay, Stephen Baker, Michael P. Weekes, Sushmita Sridhar, Nicholas M. Brown, Aminu S Jahun, Martin D. Curran, Iain Roddick, Theodore Gouliouris, Elinor Moore, M. Estée Török, Luke W. Meredith, Mark Reacher, Myra Hosmillo, Grant Hall, Laura G Caller, Sharon J. Peacock, Gordon Dougan, William L Hamilton, Sarah L Caddy, Fahad A Khokhar, Surendra Parmar, Anna Yakovleva, Ian Goodfellow, Ben Warne, Theresa Feltwell, Warne, Ben [0000-0003-1326-0373], Houldcroft, Charlotte [0000-0002-1833-5285], Hosmillo, Myra [0000-0002-3514-7681], Jahun, Aminu [0000-0002-4585-1701], Wang, Sarah [0000-0002-9790-7420], Forrest, Sally [0000-0001-6918-5216], Weekes, Michael [0000-0003-3196-5545], Baker, Stephen [0000-0003-1308-5755], Peacock, Sharon [0000-0002-1718-2782], Dougan, Gordon [0000-0003-0022-965X], Goodfellow, Ian [0000-0002-9483-510X], Apollo - University of Cambridge Repository, and Caddy, Sarah [0000-0002-9790-7420]

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, 030106 microbiology, Pneumonia, Viral, MEDLINE, Psychological intervention, Genomics, Genome, Viral, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Hospitals, University, 03 medical and health sciences, Patient safety, Betacoronavirus, Young Adult, Pandemic, Epidemiology, medicine, Infection control, Humans, Prospective Studies, Child, Pandemics, Phylogeny, Aged, Aged, 80 and over, Cross Infection, Infection Control, Whole Genome Sequencing, Transmission (medicine), business.industry, SARS-CoV-2, Infant, Newborn, COVID-19, Infant, Articles, Middle Aged, 030104 developmental biology, Infectious Diseases, England, Family medicine, Child, Preschool, Female, Patient Safety, business, Coronavirus Infections
Abstract

Background The burden and influence of health-care associated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is unknown. We aimed to examine the use of rapid SARS-CoV-2 sequencing combined with detailed epidemiological analysis to investigate health-care associated SARS-CoV-2 infections and inform infection control measures. Methods In this prospective surveillance study, we set up rapid SARS-CoV-2 nanopore sequencing from PCR-positive diagnostic samples collected from our hospital (Cambridge, UK) and a random selection from hospitals in the East of England, enabling sample-to-sequence in less than 24 h. We established a weekly review and reporting system with integration of genomic and epidemiological data to investigate suspected health-care associated COVID-19 cases. Findings Between March 13 and April 24, 2020, we collected clinical data and samples from 5613 patients with COVID-19 from across the East of England. We sequenced 1000 samples producing 747 high-quality genomes. We combined epidemiological and genomic analysis of the 299 patients from our hospital and identified 35 clusters of identical viruses involving 159 patients. 92 (58%) of 159 patients had strong epidemiological links and 32 (20%) patients had plausible epidemiological links. These results were fed back to clinical, infection control, and hospital management teams, leading to infection-control interventions and informing patient safety reporting. Interpretation We established real-time genomic surveillance of SARS-CoV-2 in a UK hospital and showed the benefit of combined genomic and epidemiological analysis for the investigation of health-care associated COVID-19. This approach enabled us to detect cryptic transmission events and identify opportunities to target infection-control interventions to further reduce health-care associated infections. Our findings have important implications for national public health policy as they enable rapid tracking and investigation of infections in hospital and community settings. Funding COVID-19 Genomics UK (supported by UK Research and Innovation, the National Institute of Health Research, the Wellcome Sanger Institute), the Wellcome Trust, the Academy of Medical Sciences and the Health Foundation, and the National Institute for Health Research Cambridge Biomedical Research Centre.

Published
2020

16. A2B-COVID: A method for evaluating potential SARS-CoV-2 transmission events

Author

Grant Hall, Christopher J. R. Illingworth, Daniela De Angelis, Stephen Baker, Kayleigh Grainger, M. Estée Török, Lucy Rivett, Aminu S Jahun, Nicholas M. Brown, Luke W. Meredith, Effrossyni Gkrania-Klotsas, Sarah L Caddy, William L Hamilton, Nick K Jones, Ashley Popay, Fahad A Khokhar, Christopher Jackson, Myra Hosmillo, Theresa Feltwell, Martin D. Curran, Sally Forest, Chris Workman, Iliana Georgana, Sushmita Sridhar, Laura G Caller, Surendra Parmar, Anna Yakovleva, Tom Dymond, Theodore Gouliouris, Dominic Sparkes, Sharon J. Peacock, Ian Goodfellow, Ben Warne, Yasmin Chaudhry, Matthew Routledge, Charlotte J. Houldcroft, Malte L Pinckert, and Michael P. Weekes

Subjects
Linkage (software), medicine.medical_specialty, Computer science, Transmission (medicine), Public health, Epidemiology, Pandemic, medicine, Data analysis, Outbreak, Computational biology, medicine.disease_cause, Coronavirus
Abstract

Identifying linked cases of infection is a key part of the public health response to viral infectious disease. Viral genome sequence data is of great value in this task, but requires careful analysis, and may need to be complemented by additional types of data. The Covid-19 pandemic has highlighted the urgent need for analytical methods which bring together sources of data to inform epidemiological investigations. We here describe A2B-COVID, an approach for the rapid identification of linked cases of coronavirus infection. Our method combines knowledge about infection dynamics, data describing the movements of individuals, and novel approaches to genome sequence data to assess whether or not cases of infection are consistent or inconsistent with linkage via transmission. We apply our method to analyse and compare data collected from two wards at Cambridge University Hospitals, showing qualitatively different patterns of linkage between cases on designated Covid-19 and non-Covid-19 wards. Our method is suitable for the rapid analysis of data from clinical or other potential outbreak settings.

Published
2020

17. Author response: Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19

Author

Simone Hargreaves, Francescsa Nice, Naidine Escoffery, Paul J. Lehner, Lucy Rivett, Caroline Saunders, Julie Harris, Neil Bartholomew, Natalia Savoinykh Yarkoni, Anne Meadows, Anne-Laure Vallier, Mary Kasanicki, Joe Marsden, Jo Wright, Charlotte J. Houldcroft, Chris Workman, Mark Ferris, Carmen M. Treacy, Kelvin Hunter, Anita Furlong, Harmeet Gill, Michael P. Weekes, Surendra Parmar, Nika Romashova, Kenneth G. C. Smith, Greg Hannon, Ashlea Bucke, Chris McNicholas, Debbie Read, Myra Hosmillo, Sushmita Sridhar, Linda Pointon, Jane Gray, John Bradley, Josh Hodgson, Emma Le Gresley, Joana Pereira-Dias, Lori Turner, Nicola Ramenatte, Stefan Gräf, Ben Warne, Claire Cormie, Jane Rowlands, Jane Kennet, Penelope-Jane Eames, Christopher Huang, Barbara J. Graves, Sally Forrest, Helen Butcher, Daniela Caputo, Joanna Calder, Anna Yakovleva, Jo Price, Aileen Narcorda, M. Estée Török, Sarah Hewitt, Martin D. Curran, Ian Goodfellow, Valentina Ruffolo, Cordova Jiménez, Michelle Wantoch, Lisa Thake, Zhen Tong, Isobel Jarvis, Laura Canna, Paul A. Lyons, Isabel Cruz, Benjamin J. Dunmore, Anne Roberts, William David Córdova Jiménez, Lucy Worboys, Helen Dolling, Rebecca Rastall, Ommar Omarjee, Sarah L Caddy, Barrie Bailey, William L Hamilton, Ekaterina Legchenko, Debra Clapham-Riley, Rachel Sutcliffe, Ciara O’Donnell, Fahad A Khokhar, Laura G Caller, Kathleen E Stirrups, Fathima Nisha Begum Samad, Hongyi Zhang, Jamie Young, Sofia Papadia, Criona O Brien, Tobias Tilly, Jennifer M. Martin, Nick K Jones, Kirsty Lagadu, Carla Ribeiro, Ailsa Bowring, Nicholas J Matheson, Tim Gould, D. Johnson, Ashley Shaw, Simon McCallum, Tim Raine, Daniel Lewis, Ariana Betancourt, Stewart Fuller, Afzal N. Chaudhry, Lenette Mactavous, Heather F Jones, William David, Rachel Doughton, Theresa Feltwell, Luke W. Meredith, Nathalie Kingston, Hannah Stark, Georgie Bowyer, Gregory J. Hannon, Karen Brookes, Dominic Sparkes, Iain Kean, Ravi Gupta, Cherry Publico, Katie Dempsey, Matthew Routledge, Nicholas K Jones, Aloka De Sa, Giles Wright, Laura Bergamaschi, Claire Mather, Rutendo Nyagumbo, Maddie Epping, Jack Levy, Marianne Perera, Christian Sparke, Fatima Nb Samad, Nicola Reynolds, Michael Gill, Hugo Tordesillas, Oisin Huhn, Anne Elmer, Geraldine Martell, Mateusz Strezlecki, Grant Hall, Andrew Hinch, Gordon Dougan, Jennifer Webster, Helen Murphy, Stephen Baker, Aminu S Jahun, Mark Toshner, Angela Wright, Natalie Quinnell, Joy Shih, Caroline Trotter, Nicholas K. Brown, Federica Mescia, John S. Bradley, and Jennifer Wood

Subjects
medicine.medical_specialty, Transmission (mechanics), Coronavirus disease 2019 (COVID-19), business.industry, law, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Period (gene), Emergency medicine, Health care, Medicine, business, law.invention
Published
2020

18. Author response: Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission

Author

Jennifer Webster, Stephen Baker, Neil Bartholomew, Aminu S Jahun, Rutendo Nyagumbo, Mark Toshner, Julie Harris, Paul J. Lehner, Charlotte J. Houldcroft, Lisa Thake, Sarah L Caddy, Benjamin J. Dunmore, Afzal N. Chaudhry, Theresa Feltwell, Christian Sparke, M. Estée Török, Nick K Jones, Michael P. Weekes, Emma Le Gresley, Simon McCallum, Tim Raine, Josefin Bartholdson Scott, Grant Hall, Myra Hosmillo, Stewart Fuller, Andrew Hinch, Angela Wright, Gordon Dougan, Jane Rowlands, Aileen Narcorda, Sally Forrest, Claire Cormie, Jennifer M. Martin, Kathleen E Stirrups, Sarah Hewitt, Natalie Quinnell, Joy Shih, Katie Dempsey, Geraldine Martell, Helen Murphy, Ashley Shaw, Cherry Publico, Heather F Jones, Carmen M. Treacy, Anne-Laure Vallier, Surendra Parmar, Jennifer Wood, Ariana Betancourt, Ashlea Bucke, Debbie Read, Helen Butcher, Martin D. Curran, Penelope-Jane Eames, Sushmita Sridhar, Chris McNicholas, Dominic Sparkes, Ian Goodfellow, Nicola Reynolds, Ciara O’Donnell, Valentina Ruffolo, Jane Kennet, Fahad A Khokhar, Hannah Stark, Paul A. Lyons, Francescsa Nice, Karen Brookes, Lenette Mactavous, Claire Mather, Maddie Epping, Aloka De Sa, Lucy Warboys, Isabel Cruz, Naidine Escoffery, Carla Ribeiro, Ailsa Bowring, Nicholas J Matheson, Iain Kean, Tobias Tilly, Daniel Lewis, Ravi Gupta, Kelvin Hunter, Giles Wright, Anne Roberts, Hugo Tordesillas, Isobel Jarvis, Nicholas K. Brown, Laura Bergamaschi, Anne Elmer, Harmeet Gill, Oisin Huhn, D. Johnson, Laura G Caller, John Bradley, Caroline Saunders, Federica Mescia, Joanna Calder, Anna Yakovleva, Jo Price, Richard J. Samworth, Kenneth G. C. Smith, Mary Kasanicki, Hongyi Zhang, Laura Canna, Rebecca Rastall, Jo Wright, Ben Warne, Simone Hargreaves, Anita Furlong, Josh Hodgson, Daniela Caputo, Stefan Gräf, Jamie Young, Sofia Papadia, Criona O Brien, Kirsty Lagadu, Georgie Bowyer, Michelle Wantoch, Ekaterina Legchenko, Debra Clapham-Riley, Rachel Sutcliffe, Joe Marsden, Mark Ferris, Tim Gould, Mailis Maes, Luke W. Meredith, Joana Pereira-Dias, Nicola Ramenatte, Matthew Routledge, Nathalie Kingston, Helen Dolling, William L Hamilton, Linda Pointon, Christopher Huang, Barbara J. Graves, Lucy Rivett, Anne Meadows, and Zhen Tong

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Asymptomatic, law.invention, Carriage, Transmission (mechanics), law, Health care, medicine, medicine.symptom, Intensive care medicine, business
Published
2020

19. Murine norovirus virulence factor 1 (VF1) protein contributes to viral fitness during persistent infection

Author

Ian Goodfellow, Constantina Borg, Frédéric Sorgeloos, Lucy Thorne, Aminu S Jahun, Dalan Bailey, Jahun, Aminu [0000-0002-4585-1701], Goodfellow, Ian [0000-0002-9483-510X], and Apollo - University of Cambridge Repository

Subjects
Male, Virulence Factors, ved/biology.organism_classification_rank.species, Apoptosis, Biology, Virus Replication, Virulence factor, Virus, Cell Line, viral persistence, Pathogenesis, Mice, Viral Proteins, 03 medical and health sciences, Immune system, Virology, RNA Viruses, Animals, Caliciviridae Infections, 030304 developmental biology, 0303 health sciences, Innate immune system, Virulence, Animal, 030306 microbiology, ved/biology, accessory protein, Norovirus, Interferon-beta, Immunity, Innate, Reverse genetics, Virus Shedding, 3. Good health, Mice, Inbred C57BL, Open reading frame, interferon response, VF1, Viral load, Murine norovirus
Abstract

BackgroundMurine norovirus (MNV) is widely used as a model for studying norovirus biology. While MNV isolates vary in their pathogenesis, infection of immunocompetent mice mostly results in persistent infection. The ability of a virus to establish a persistent infection is dependent on its ability to subvert or avoid the host immune response. Previously, we described the identification and characterization of virulence factor 1 (VF1) in MNV, and established that it acts as an innate immune antagonist. Here, we explore the role of VF1 during persistent MNV infection in an immunocompetent host.MethodsUsing reverse genetics, we generated VF1-knockout MNV-3 that contained a single or a triple termination codon inserted in the VF1 open reading frame.ResultsVF1-knockout MNV-3 replicated to comparable levels to the wildtype virus in tissue culture. Comparative studies between MNV-3 and an acute MNV-1 strain show that MNV-3 VF1 exerts the same functions as MNV-1 VF1, but with reduced potency. Mice infected with VF1-knockout MNV-3 showed significantly reduced replication kinetics during the acute phase of the infection, but viral loads rapidly reached the levels seen in mice infected with wildtype virus after phenotypic restoration of VF1 expression. Infection with an MNV-3 mutant that had three termination codons inserted into VF1, in which reversion was suppressed, resulted in consistently lower replication throughout a three-month persistent infection in mice, suggesting a role for VF1 in viral fitness in vivo.ConclusionOur results indicate that VF1 expressed by a persistent strain of MNV also functions to antagonise the innate response to infection. We found that VF1 is not essential for viral persistence, but instead contributes to viral fitness in mice. These data fit with the hypothesis that noroviruses utilise multiple mechanisms to avoid and/or control the host response to infection and that VF1 is just one component of this.

Published
2019

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