Rachel Williams

University College London

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Judith Breuer

University College London

Sunando Roy

University College London

Julianne R. Brown

Great Ormond Street Hospital for Children NHS Foundation Trust

Thushan I. de Silva

University of Sheffield

Emma C. Thomson

University of Glasgow

David G. Partridge

Sheffield Teaching Hospitals NHS Foundation Trust

Charlotte A. Williams

University College London

Tabitha Mahungu

Royal Free London NHS Foundation Trust

Alison Holmes

National Institute for Health Research

Gaia Nebbia

Guy's and St Thomas' NHS Foundation Trust

Cooperative Institutions

Imperial College London

613

Wellcome Sanger Institute

476

University of Cambridge

474

University College London

418

University of Oxford

307

University of Edinburgh

289

International Severe Acute Respiratory and Emerging Infection Consortium

289

Quadram Institute

269

National and Kapodistrian University of Athens

265

St Mary's Hospital

243

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Urine N-Acetylaspartate Distinguishes Phenotypes in Canavan Disease

Human Gene Therapy (2024)

Amanda Nagy Florian Eichler Annette Bley Jan Bredow Alexander Fay

Canavan disease (CD) is an ultra-rare autosomal recessive leukodystrophy caused by loss-of-function mutations in ASPA, which encodes aspartoacylase (ASPA), leading to accumulation of N-acetylaspartate (NAA). Patients with CD typically present with profound psychomotor deficits within the first 6 months of life and meet few motor milestones. Within CD a subset of patients exhibits a milder phenotype with more milestone acquisition, possibly related to greater residual ASPA activity. An ongoing CD natural history study and a literature search were leveraged to compare urine NAA levels and associated genotypes in patients classified with mild or typical CD, with the hypothesis that urine NAA levels reflect ASPA activity and therefore can distinguish between the two phenotypes. Urine NAA levels were lower, on average (p < 0.0001), in individuals with mild (mean 525.3, range 25.2-1,335 mmol/mol creatinine [Cr]) compared with typical CD (mean 1,369, range 391.7-2,420 mmol/mol Cr). Mutations R71H and Y288C, variants that may harbor residual ASPA activity, were unique to the mild phenotype population (56%, 14/25) and not found in individuals with a typical phenotype (0%, 0/39). In aggregate, urine NAA levels can distinguish between mild and typical CD phenotypes, suggesting the ability to reflect ASPA activity.

10.1089/hum.2024.168

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SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men

medRxiv (Cold Spring Harbor Laboratory) (2021)

Oliver Stirrup Florencia A. T. Boshier Cristina Venturini José Afonso Guerra‐Assunção Adela Alcolea-Medina

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. Methods We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16/11/2020 - 10/01/2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. Results Sequences were obtained from 2341 inpatients (HOCI cases = 786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The hazard ratio (HR) for mortality of B.1.1.7 compared to other lineages was 1.01 (95% CI 0.79-1.28, P=0.94) and for ITU admission was 1.01 (95% CI 0.75-1.37, P=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95-1.78) and ITU admission (HR 1.82, 95% CI 1.15-2.90) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61-1.10; ITU HR 0.74, 95% CI 0.52-1.04). Conclusions In common with smaller studies of patients hospitalised with SARS-CoV-2 we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared to other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.

10.1101/2021.06.24.21259107

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Evaluating the cost implications of integrating SARS-CoV-2 genome sequencing for infection prevention and control investigation of nosocomial transmission within hospitals

Journal of Hospital Infection (2023)

Monica Panca James Blackstone Oliver Stirrup M.-T. Cutino-Moguel Emma C. Thomson

The COG-UK hospital-onset COVID-19 infection (HOCI) trial evaluated the impact of SARS-CoV-2 whole-genome sequencing (WGS) on acute infection, prevention, and control (IPC) investigation of nosocomial transmission within hospitals.

10.1016/j.jhin.2023.06.005

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Proinflammatory cytokines and HIV‐1 synergistically enhance CXCL10 expression in human astrocytes

Glia (2008)

Rachel Williams Navneet K. Dhillon Sonia T. Hegde Hong-Hong Yao Fuwang Peng

Abstract HIV encephalitis (HIVE), the pathologic correlate of HIV‐associated dementia (HAD) is characterized by astrogliosis, cytokine/chemokine dysregulation, and neuronal degeneration. Increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD. In fact, the severity of HAD/HIVE correlates more closely with the presence of activated glial cells than with the presence and amount of HIV‐infected cells in the brain. Astrocytes, the most numerous cell type within the brain, provide an important reservoir for the generation of inflammatory mediators, including interferon‐γ inducible peptide‐10 (CXCL10), a neurotoxin and a chemoattractant, implicated in the pathophysiology of HAD. Additionally, the proinflammatory cytokines, IFN‐γ and TNF‐α, are also markedly increased in CNS tissues during HIV‐1 infection. In this study, we hypothesized that the interplay of host cytokines and HIV‐1 could lead to enhanced expression of the toxic chemokine, CXCL10. Our findings demonstrate a synergistic induction of CXCL10 mRNA and protein in human astrocytes exposed to HIV‐1 and the proinflammatory cytokines. Signaling molecules, including JAK, STATs, MAPK (via activation of Erk1/2, AKT, and p38), and NF‐κB were identified as instrumental in the synergistic induction of CXCL10. Understanding the mechanisms involved in HIV‐1 and cytokine‐mediated up‐regulation of CXCL10 could aid in the development of therapeutic modalities for HAD. © 2008 Wiley‐Liss, Inc.

Proinflammatory cytokine

Astrogliosis

10.1002/glia.20801

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Citations (72)

Genomic investigations of unexplained acute hepatitis in children

Nature (2023)

Sofia Morfopoulou Sarah Buddle Oscar Enrique Torres Montaguth Laura Atkinson José Afonso Guerra‐Assunção

Abstract Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Acute hepatitis

10.1038/s41586-023-06003-w

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Citations (92)

Mechanisms of platelet‐derived growth factor‐mediated neuroprotection – implications in HIV dementia

European Journal of Neuroscience (2008)

Fuwang Peng Navneet K. Dhillon Honghong Yao Xuhui Zhu Rachel Williams

Platelet-derived growth factor (PDGF) has been implicated in promoting survival and proliferation of immature neurons, and even protecting neurons from gp120-induced cytotoxicity. However, the mechanisms involved in neuroprotection are not well understood. In the present study we demonstrate the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-mediated neuroprotection. Pharmacological inhibition of PI3K greatly reduced the ability of PDGF-BB to block gp120 IIIB-mediated apoptosis and cell death in human neuroblastoma cells. The role of Akt in PDGF-mediated protection was further corroborated using a dominant-negative mutant of Akt, which was able to block the protective effect of PDGF. We next sequentially examined the signals downstream of Akt in PDGF-mediated protection in human neuroblastoma cells. In cells pretreated with PDGF prior to gp120 there was increased phosphorylation of both GSK-3beta and Bad, an effect that was inhibited by PI3-kinase inhibitor. Nuclear translocation of NF-kappaB, which lies downstream of GSK-3beta, however, remained unaffected in cells treated with PDGF. In addition to inducing phosphorylation of Bad, PDGF-mediated protection also involved down-regulation of the proapoptotic protein Bax. Furthermore, PDGF-mediated protection also involved the inhibition of gp120-induced release of mitochondrial cytochrome C. Our findings thus underscore the roles of both PI3K/Akt and Bcl family pathways in PDGF-mediated neuroprotection.

10.1111/j.1460-9568.2008.06444.x

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Citations (39)

The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study

Journal of Infection (2021)

Florencia A. T. Boshier Cristina Venturini Oliver Stirrup José Afonso Guerra‐Assunção Adela Alcolea-Medina

ObjectivesRecently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals.MethodsWe collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences.ResultsMixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages.ConclusionsWe find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.

Lineage (genetic)

Pandemic

10.1016/j.jinf.2021.09.022

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Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus

Frontiers in Microbiology (2016)

Charlotte J. Houldcroft Josephine M. Bryant Daniel P. Depledge Ben Margetts Jacob Simmonds

Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.

Cytomegalovirus

10.3389/fmicb.2016.01317

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Citations (79)

Advances in our understanding of the bone and joint pathology caused by Staphylococcus aureus infection

Lara D. Veeken (2000)

Sean P. Nair Rachel Williams Brian E. Henderson

Joint infections

10.1093/rheumatology/39.8.821

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Citations (46)

Whole genome sequencing Mycobacterium tuberculosis directly from sputum identifies more genetic diversity than sequencing from culture

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Camus Nimmo Liam P. Shaw Ronan Doyle Rachel Williams Kayleen Brien

Abstract Background Repeated culture reduces within-sample Mycobacterium tuberculosis genetic diversity due to selection of clones suited to growth in culture and/or random loss of lineages, but it is not known to what extent omitting the culture step altogether alters genetic diversity. We compared M. tuberculosis whole genome sequences generated from 33 paired clinical samples using two methods. In one method DNA was extracted directly from sputum then enriched with custom-designed SureSelect (Agilent) oligonucleotide baits and in the other it was extracted from mycobacterial growth indicator tube (MGIT) culture. Results DNA directly sequenced from sputum showed significantly more within-sample diversity than that from MGIT culture (median 5.0 vs 4.5 heterozygous alleles per sample, p=0.04). Resistance associated variants present as HAs occurred in four patients, and in two cases may provide a genotypic explanation for phenotypic resistance. Conclusions Culture-free M. tuberculosis whole genome sequencing detects more within-sample diversity than a leading culture-based method and may allow detection of mycobacteria that are not actively replicating.

Sputum culture

10.1101/446849

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Citations (1)