A5087666817- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- Animal Virus Infections Studies
- SARS-CoV-2 and COVID-19 Research
- Virus-based gene therapy research
- SARS-CoV-2 detection and testing
- COVID-19 Clinical Research Studies
- COVID-19 epidemiological studies
- Geriatric Care and Nursing Homes
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- Herpesvirus Infections and Treatments
- Evolution and Genetic Dynamics
- CRISPR and Genetic Engineering
- Cancer-related gene regulation
- Parvovirus B19 Infection Studies
- Plant Virus Research Studies
- interferon and immune responses
- Vector-Borne Animal Diseases
- Respiratory viral infections research
- Ubiquitin and proteasome pathways
- Cytomegalovirus and herpesvirus research
- Genetics, Bioinformatics, and Biomedical Research
- Frailty in Older Adults
- Long-Term Effects of COVID-19
University of Cambridge
2013-2023
Addenbrooke's Hospital
2014-2023
Imperial College London
2006-2022
Quadram Institute
2022
University College Dublin
2020
KU Leuven
2018
University of Warwick
2008
University of Edinburgh
2008
Weatherford College
2006
Lindsay Unified School District
2006
Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe identification and characterization a novel open reading frame (ORF4) encoded by murine norovirus (MNV) subgenomic RNA, in an alternative overlapping VP1 coding region. ORF4 is translated during virus infection resultant protein localizes predominantly mitochondria. Using reverse genetics demonstrated that expression not required for replication tissue culture but its loss results...
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around world. The modest mutation rate rapid prevents reconstruction from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe patterns in 1181 samples sequenced to high depth duplicate. 95.1% show mutations at detectable allele frequencies. Analyses mutational spectra revealed strong...
ABSTRACT The replication of poliovirus, a positive-stranded RNA virus, requires translation the infecting genome followed by virus-encoded VPg and 3D polymerase-primed synthesis negative-stranded template. sequences involved in latter process are poorly defined. Since many picornavirus form structures, we searched genome, other than untranslated regions, for predicted local secondary structural elements identified 61-nucleotide (nt) stem-loop region encoding 2C protein. Covariance analysis...
Human noroviruses (HuNoV) are a leading cause of viral gastroenteritis worldwide and significant morbidity mortality in all age groups. The recent finding that HuNoV can be propagated B cells mucosa-derived intestinal epithelial organoids (IEOs) has transformed our ability to dissect the life cycle noroviruses. Using transcriptome sequencing (RNA-Seq) HuNoV-infected (IECs), we have found replication IECs results interferon (IFN)-induced transcriptional responses is sensitive IFN. This...
The BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) is being utilised internationally for mass vaccination. Evidence of single-dose protection against symptomatic disease has encouraged some countries to opt delayed booster doses BNT162b2, but the effect this strategy on rates asymptomatic SARS-CoV-2 infection remains unknown. We previously demonstrated frequent pauci- and amongst healthcare workers (HCWs) during UK’s first wave pandemic, using a comprehensive PCR-based HCW screening...
COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms common, seemingly unrelated to severity. The true frequency underlying mechanisms of injury are unknown, but exaggerated host inflammatory responses appear be key driver We investigated the dynamics of, relationship between, serum markers brain [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) total tau]...
Understanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 isolates from the University of Cambridge 5 October 6 December 2020. We perform a detailed phylogenetic comparison with 972 surrounding community, complemented epidemiological contact tracing data, determine dynamics. observe limited viral introductions university; majority student cases were linked single genetic...
The cGAS-STING pathway is central to the interferon response against DNA viruses. However, recent studies are increasingly demonstrating its role in restriction of some RNA Here, we show that also contributes noroviruses, currently commonest causes infectious gastroenteritis worldwide. We a significant reduction interferon-β induction and corresponding increase viral replication norovirus-infected cells after deletion STING, cGAS, or IFI16. Further, find immunostimulatory host genome-derived...
Two classes of viruses, namely members the Potyviridae and Caliciviridae, use a novel mechanism for initiation protein synthesis that involves interaction translation factors with viral covalently linked to RNA, known as VPg. The calicivirus VPg proteins can interact directly eIF4E eIF3. Translation on feline (FCV) RNA requires because it is inhibited by recombinant 4E-BP1. However, date, there have been no functional studies carried out respect norovirus initiation, lack suitable source...
The mechanism and role of RNA structure elements in the replication translation Caliciviridae remains poorly understood. Several algorithmically independent methods were used to predict secondary structures within Norovirus, Sapovirus, Vesivirus Lagovirus genera. All showed profound suppression synonymous site variability (SSSV) at genomic 5′ ends start sub-genomic (sg) transcript, consistent with evolutionary constraints from underlying structure. A newly developed thermodynamic scanning...
Despite the significant disease burden caused by human norovirus infection, an efficient tissue-culture system for these viruses remains elusive. Murine (MNV) is ideal surrogate study of biology, as virus replicates efficiently in tissue culture and a low-cost animal model readily available. In this report, reverse-genetics MNV described, using fowlpox (FWPV) recombinant expressing T7 RNA polymerase to recover genetically defined first time. These studies demonstrated that approaches have...
Background. Noroviruses are a highly transmissible and major cause of nosocomial gastroenteritis resulting in bed hospital-ward closures. Where hospital outbreaks suspected, it is important to determine the routes spread so that appropriate infection-control procedures can be implemented. To investigate cluster norovirus cases occurring children undergoing bone marrow transplant, we undertook genome sequencing by next-generation methods. Detailed comparison sequence data from 2 linked...
Human noroviruses are one of the major causes acute gastroenteritis in developed world, yet our understanding their molecular mechanisms genome translation and replication lags behind that for many RNA viruses. Due to nonculturable nature human noroviruses, related members Caliciviridae family small viruses often used as model systems dissect finer details norovirus life cycle. Murine (MNV) has provided such system with which study basic cell culture. In this report we describe use...
Knowledge of the host factors required for norovirus replication has been hindered by challenges associated with culturing human noroviruses. We have combined proteomic analysis viral translation and complexes a CRISPR screen, to identify infection. The core stress granule component G3BP1 was identified as factor essential efficient murine infection, demonstrating conserved function across Norovirus genus. Furthermore, we show that functions in novel paradigm VPg-dependent initiation,...
SARS-CoV-2 is notable both for its rapid spread, and the heterogeneity of patterns transmission, with multiple published incidences superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer viral transmission occurring between patients health care workers (HCWs) in largest clusters COVID-19 infection identified during first wave epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates individuals reporting symptoms, recorded...
Epidermal growth factor-like (EGF) and short consensus repeat (SCR) domains are commonly found in cell surface soluble proteins that mediate specific protein-protein recognition events. Unlike the immunoglobulin (Ig) superfamily, very little is known about general properties of intermolecular interactions encoded by these common modules, particular, how specificity binding achieved. We have dissected CD97 (a member EGF-TM7 family) to complement regulator CD55, two modular contain EGF SCR...
Murine norovirus (MNV), identified in 2003, is the only which replicates efficiently tissue culture and as a result has been used extensively model for human noroviruses, major cause of acute gastroenteritis. The current report describes generation new approach to reverse genetics recovery genetically defined MNV that relies on transfection vitro transcribed capped RNA directly into cells. use recently developed ScriptCap post-transcriptional enzymatic capping system, followed by optimized...
Human noroviruses (HuNoV) are a major cause of viral gastroenteritis worldwide, yet, due to the inability propagate HuNoV in cell culture, murine norovirus (MNV) is typically used as surrogate study biology. MNV-3 represents an attractive strain infections vivo because it establishes persistence wild-type mice, yet causes symptoms resembling immune-compromised STAT1 −/− mice. The lack reverse-genetics approaches recover genetically defined has limited further studies on identification...
Viruses have evolved a variety of mechanisms to usurp the host cell translation machinery enable viral genome in presence high levels cellular mRNAs. Noroviruses, major cause gastroenteritis man, mechanism that relies on interaction initiation factors with virus-encoded VPg protein covalently linked 5' end RNA. To further characterize this novel initiation, we used proteomics identify components norovirus factor complex. This approach revealed binds directly eIF4F complex, affinity occurring...
ABSTRACT The Caliciviridae family comprises positive-sense RNA viruses of medical and veterinary significance. In humans, caliciviruses are a major cause acute gastroenteritis, while in animals respiratory illness, conjunctivitis, stomatitis, hemorrhagic disease documented. Investigation virus-host interactions is limited by lack culture systems for many this family. Feline calicivirus (FCV), member the Vesivirus genus, provides tractable model, since it may be propagated cell culture....
ABSTRACT We report the solution structures of VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV), which have been determined by nuclear magnetic resonance spectroscopy. In both cases, core protein adopts a compact helical structure flanked flexible N C termini. Remarkably, while FCV contains well-defined three-helix bundle, MNV has just first two these secondary elements. cores are stabilized networks hydrophobic salt bridge interactions. The Tyr residue in that is...