Publications
100 results found
Townsley H, Gahir J, Russell TW, et al., 2024, COVID-19 in non-hospitalised adults caused by either SARS-CoV-2 sub-variants Omicron BA.1, BA.2, BA.4/5 or Delta associates with similar illness duration, symptom severity and viral kinetics, irrespective of vaccination history., PLoS One, Vol: 19
BACKGROUND: SARS-CoV-2 variant Omicron rapidly evolved over 2022, causing three waves of infection due to sub-variants BA.1, BA.2 and BA.4/5. We sought to characterise symptoms and viral loads over the course of COVID-19 infection with these sub-variants in otherwise-healthy, vaccinated, non-hospitalised adults, and compared data to infections with the preceding Delta variant of concern (VOC). METHODS: In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive polymerase chain reaction (PCR) or lateral flow test, self-swabbed on alternate weekdays until day 10. We compared participant-reported symptoms and viral load trajectories between infections caused by VOCs Delta and Omicron (sub-variants BA.1, BA.2 or BA.4/5), and tested for relationships between vaccine dose, symptoms and PCR cycle threshold (Ct) as a proxy for viral load using Chi-squared (χ2) and Wilcoxon tests. RESULTS: 563 infection episodes were reported among 491 participants. Across infection episodes, there was little variation in symptom burden (4 [IQR 3-5] symptoms) and duration (8 [IQR 6-11] days). Whilst symptom profiles differed among infections caused by Delta compared to Omicron sub-variants, symptom profiles were similar between Omicron sub-variants. Anosmia was reported more frequently in Delta infections after 2 doses compared with Omicron sub-variant infections after 3 doses, for example: 42% (25/60) of participants with Delta infection compared to 9% (6/67) with Omicron BA.4/5 (χ2 P < 0.001; OR 7.3 [95% CI 2.7-19.4]). Fever was less common with Delta (20/60 participants; 33%) than Omicron BA.4/5 (39/67; 58%; χ2 P = 0.008; OR 0.4 [CI 0.2-0.7]). Amongst infections with an Omicron sub-variants, symptoms of coryza, fatigue, cough and myalgia predominated. Viral load trajectories and peaks did not differ between Delta, and Omicron, irrespective of symptom severity (including asymptomatic participants), VOC or vaccination status. PCR Ct val
Cocozza F, Martin-Jaular L, Lippens L, et al., 2023, Extracellular vesicles and co-isolated endogenous retroviruses from murine cancer cells differentially affect dendritic cells., EMBO J, Vol: 42
Cells secrete extracellular vesicles (EVs) and non-vesicular extracellular (nano)particles (NVEPs or ENPs) that may play a role in intercellular communication. Tumor-derived EVs have been proposed to induce immune priming of antigen presenting cells or to be immuno-suppressive agents. We suspect that such disparate functions are due to variable compositions in EV subtypes and ENPs. We aimed to characterize the array of secreted EVs and ENPs of murine tumor cell lines. Unexpectedly, we identified virus-like particles (VLPs) from endogenous murine leukemia virus in preparations of EVs produced by many tumor cells. We established a protocol to separate small EVs from VLPs and ENPs. We compared their protein composition and analyzed their functional interaction with target dendritic cells. ENPs were poorly captured and did not affect dendritic cells. Small EVs specifically induced dendritic cell death. A mixed large/dense EV/VLP preparation was most efficient to induce dendritic cell maturation and antigen presentation. Our results call for systematic re-evaluation of the respective proportions and functions of non-viral EVs and VLPs produced by murine tumors and their contribution to tumor progression.
Kazachenka A, Loong JH, Attig J, et al., 2023, The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes, NAR Cancer, Vol: 5, Pages: 1-20, ISSN: 2632-8674
Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.
Vinuesa CG, Grenov A, Kassiotis G, 2023, Innate virus-sensing pathways in B cell systemic autoimmunity, SCIENCE, Vol: 380, Pages: 478-484, ISSN: 0036-8075
Ng K, Boumelha J, Enfield KSS, et al., 2023, Antibodies against endogenous retroviruses promote lung cancer immunotherapy, NATURE, Vol: 616, Pages: 563-+, ISSN: 0028-0836
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- Citations: 11
Fernandes LP, Enriquez-Gasca R, Gould PA, et al., 2022, A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819., Sci Adv, Vol: 8
Mammalian genomes are a battleground for genetic conflict between repetitive elements and KRAB-zinc finger proteins (KZFPs). We asked whether KZFPs can regulate cell fate by using ZFP819, which targets a satellite DNA array, ZP3AR. ZP3AR coats megabase regions of chromosome 7 encompassing genes encoding ZSCAN4, a master transcription factor of totipotency. Depleting ZFP819 in mouse embryonic stem cells (mESCs) causes them to transition to a 2-cell (2C)-like state, whereby the ZP3AR array switches from a poised to an active enhancer state. This is accompanied by a global erosion of heterochromatin roadblocks, which we link to decreased SETDB1 stability. These events result in transcription of active LINE-1 elements and impaired differentiation. In summary, ZFP819 and TRIM28 partner up to close chromatin across Zscan4, to promote exit from totipotency. We propose that satellite DNAs may control developmental fate transitions by barcoding and switching off master transcription factor genes.
Jiao H, Wachsmuth L, Wolf S, et al., 2022, ADAR1 averts fatal type I interferon induction by ZBP1, NATURE, Vol: 607, Pages: 776-+, ISSN: 0028-0836
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- Citations: 43
Ng KW, Faulkner N, Finsterbusch K, et al., 2022, SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies, SCIENCE TRANSLATIONAL MEDICINE, Vol: 14, ISSN: 1946-6234
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- Citations: 32
Fendler A, Shepherd STC, Au L, et al., 2021, Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study, Nature Cancer, Vol: 2, Pages: 1305-1320, ISSN: 2662-1347
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Fendler A, Au L, Shepherd STC, et al., 2021, Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study, Nature Cancer, Vol: 2, Pages: 1321-1337, ISSN: 2662-1347
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Ottina E, Panova V, Doglio L, et al., 2021, E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion, ONCOGENE, Vol: 40, Pages: 5567-5578, ISSN: 0950-9232
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- Citations: 2
Au L, Fendler A, Shepherd STC, et al., 2021, Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2, Nature Medicine, Vol: 27, Pages: 1362-1366, ISSN: 1078-8956
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.
Faulkner N, Ng KW, Wu MY, et al., 2021, Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains, ELIFE, Vol: 10, ISSN: 2050-084X
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- Citations: 27
Danelli L, Cornish G, Merkenschlager J, et al., 2021, Default polyfunctional T helper 1 response to ample signal 1 alone, CELLULAR & MOLECULAR IMMUNOLOGY, Vol: 18, Pages: 1809-1822, ISSN: 1672-7681
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- Citations: 2
Ng KW, Faulkner N, Wrobel AG, et al., 2021, Heterologous humoral immunity to human and zoonotic coronaviruses: Aiming for the achilles heel, SEMINARS IN IMMUNOLOGY, Vol: 55, ISSN: 1044-5323
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- Citations: 9
Rosa A, Pye VE, Graham C, et al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
Buck MD, Poirier EZ, Cardoso A, et al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay [version 1; peer review: 2 approved with reservations], Wellcome Open Research, Vol: 6, Pages: 1-29
Abstract The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARSCoV-2 detection by RT-LAMP in 25 minutes that is robust, reliable, repeatable, sensitive, specific, and inexpensive
Buck MD, Poirier EZ, Cardoso A, et al., 2021, SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay., Wellcome Open Res, Vol: 6, ISSN: 2398-502X
The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP that is robust, reliable, repeatable, specific, and inexpensive.
Ng KW, Faulkner N, Cornish GH, et al., 2020, Preexisting and de novo humoral immunity to SARS-CoV-2 in humans, Science, Vol: 370, Pages: 1339-1343, ISSN: 0036-8075
Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)–reactive antibodies were detectable using a flow cytometry–based method in SARS-CoV-2–uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S–reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2–uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
Ng KW, Attig J, Bolland W, et al., 2020, Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option, NATURE GENETICS, Vol: 52, Pages: 1294-1302, ISSN: 1061-4036
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- Citations: 60
Aitken J, Ambrose K, Barrell S, et al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center (vol 47, pg 613, 2020), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 1000-1000, ISSN: 1087-0156
Houlihan CF, Vora N, Byrne T, et al., 2020, Pandemic peak SARS-CoV-2 infection and seroconversion rates in London frontline health-care workers, LANCET, Vol: 396, Pages: E6-E7, ISSN: 0140-6736
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- Citations: 131
Toboso-Navasa A, Gunawan A, Morlino G, et al., 2020, Restriction of memory B cell differentiation at the germinal center B cell positive selection stage., J Exp Med, Vol: 217
Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.
Aitken J, Ambrose K, Barrell S, et al., 2020, Scalable and robust SARS-CoV-2 testing in an academic center, Nature Biotechnology, Vol: 38, Pages: 927-931, ISSN: 1087-0156
Panova V, Attig J, Young GR, et al., 2020, Antibody-induced internalisation of retroviral envelope glycoproteins is a signal initiation event, PLOS PATHOGENS, Vol: 16, ISSN: 1553-7366
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- Citations: 7
Jiao H, Wachsmuth L, Kumari S, et al., 2020, Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation, NATURE, Vol: 580, Pages: 391-+, ISSN: 0028-0836
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- Citations: 19
Sledzinska A, de Mucha MV, Bergerhoff K, et al., 2020, Regulatory T Cells Restrain Interleukin-2-and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4<SUP>+</SUP> T Cells, IMMUNITY, Vol: 52, Pages: 151-+, ISSN: 1074-7613
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- Citations: 96
Kazachenka A, Young GR, Attig J, et al., 2019, Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression, GENOME MEDICINE, Vol: 11, ISSN: 1756-994X
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- Citations: 15
Ng KW, Attig J, Young GR, et al., 2019, Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist, ELIFE, Vol: 8, ISSN: 2050-084X
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- Citations: 35
Attig J, Young GR, Hosie L, et al., 2019, LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly, Genome Research, Vol: 29, Pages: 1578-1590, ISSN: 1054-9803
Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.
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