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Voyage of the Frostheart
\"In a snow-covered land where monsters rule the icy tundra, only song weavers hold the power to control these vicious giants. But for centuries song weavers have been the subject of suspicion--how can those who hold so much power be trusted? Ever since his parents were lost on a pathfinding expedition, Ash has spent his life as an outcast. As a budding song weaver, his village marked him as a potential threat, even though all he wants to do is protect them. Eager to find his place in the world, he and his cantankerous yeti caretaker seek passage on the Frostheart: a ship-like sleigh whose mission is to explore faraway lands. There he meets a fast-talking, spunky navigator, a walrus captain with a peg leg who runs a tight sleigh, and a mysterious traveler who encourages him to hone his song. But can Ash's song weaving save the Frostheart from the monsters hiding under the ice? Or will his untamed powers put his newfound friends in jeopardy?\"-- Publisher marketing.
Book
Inside-out: Antibody-binding reveals potential folding hinge-points within the SARS-CoV-2 replication co-factor nsp9
Nsp9 is a conserved accessory component of the coronaviral replication and transcription complex. It is the predominant substrate of nsp12’s nucleotidylation activity while also serving to recruit proteins required for viral 5’-capping. Anti-nsp9 specific nanobodies have been isolated previously. We confirm that their binding mode is centred upon Trp-53 within SARS-CoV-2 nsp9. Antibody binding at this site surprisingly results in large-scale changes to the overall topology of this coronaviral unique fold. We further characterise the antibody-induced structural dynamism within nsp9, identifying a number of potentially flexible regions. A large expansion of the cavity between the s2-s3 and s4-s5 loops is particularly noteworthy. As is the potential for large-scale movements in the C-terminal GxxxG helix.
Journal Article
مغامرة رعد مع قراصنة المجرات
قصة (مغامرة رعد مع قراصنة المجرات) والتي قامت بتأليفها (إيلا دينتون) في حوالي (26) من القطع المتوسط تحكي أنه بدا كل شيء مسالما وهادئا في الفضاء الخارجي، حتى سرقت مجموعة من القراصنة القمر ! هل سيجد رعد وصديقه الـمخلص القط فهد طريقهما لإنقاذ القمر ؟ أم سينتهي الأمر بهما بالمشي على اللوح الخشبي الفضائي ؟
BOOK
CD8+ T-cell responses towards conserved influenza B virus epitopes across anatomical sites and age
Influenza B viruses (IBVs) cause substantive morbidity and mortality, and yet immunity towards IBVs remains understudied. CD8
+
T-cells provide broadly cross-reactive immunity and alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted by 5 HLAs have been identified currently. A broader array of conserved IBV T-cell epitopes is needed to develop effective cross-reactive T-cell based IBV vaccines. Here we identify 9 highly conserved IBV CD8
+
T-cell epitopes restricted to HLA-B*07:02, HLA-B*08:01 and HLA-B*35:01. Memory IBV-specific tetramer
+
CD8
+
T-cells are present within blood and tissues. Frequencies of IBV-specific CD8
+
T-cells decline with age, but maintain a central memory phenotype. HLA-B*07:02 and HLA-B*08:01-restricted NP
30-38
epitope-specific T-cells have distinct T-cell receptor repertoires. We provide structural basis for the IBV HLA-B*07:02-restricted NS1
196-206
(11-mer) and HLA-B*07:02-restricted NP
30-38
epitope presentation. Our study increases the number of IBV CD8
+
T-cell epitopes, and defines IBV-specific CD8
+
T-cells at cellular and molecular levels, across tissues and age.
Influenza B viruses are linked to significant morbidity and mortality, and yet their immunobiology is comparatively poorly understood. Here Menon
et al
identify influenza B virus-specific CD8
+
T cell epitopes and characterise these in adults, children and the elderly.
Journal Article
Recognition of the antigen-presenting molecule MR1 by a Vδ3⁺ γδ T cell receptor
Unlike conventional αβ T cells, γδ T cells typically recognize non-peptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1⁺ and Vδ2⁺ γδ TCR-mediated ligand recognition, the mode of Vδ3⁺ TCR ligand engagement is unknown. MHC class I–related protein, MR1, presents vitamin B metabolites to αβ T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2⁻ γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3⁺ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3⁺ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.
Journal Article
Structure of a fully assembled γδ T cell antigen receptor
T cells in jawed vertebrates comprise two lineages, αβ T cells and γδ T cells, defined by the antigen receptors they express—that is, αβ and γδ T cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring that γδ TCRs recognize more structurally diverse ligands
1
. Nevertheless, the receptors use shared CD3 subunits to initiate signalling. Whereas the structural organization of αβ TCRs is understood
2
,
3
, the architecture of γδ TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully assembled, MR1-reactive, human Vγ8Vδ3 TCR–CD3δγε
2
ζ
2
complex bound by anti-CD3ε antibody Fab fragments
4
,
5
. The arrangement of CD3 subunits in γδ and αβ TCRs is conserved and, although the transmembrane α-helices of the TCR-γδ and -αβ subunits differ markedly in sequence, packing of the eight transmembrane-helix bundles is similar. However, in contrast to the apparently rigid αβ TCR
2
,
3
,
6
, the γδ TCR exhibits considerable conformational heterogeneity owing to the ligand-binding TCR-γδ subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transfer of the Vγ8Vδ3 TCR variable domains to an αβ TCR enhanced receptor signalling, suggesting that γδ TCR organization reflects a compromise between efficient signalling and the ability to engage structurally diverse ligands. Our findings reveal the marked structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signalling as either a rigid or flexible structure.
Cryogenic electron microscopy determines the structure of a fully assembled, MR1-reactive, human Vγ8Vδ3 TCR–CD3δγε
2
ζ
2
complex bound by anti-CD3ε antibody Fab fragments.
Journal Article
Mapping the immunopeptidome of seven SARS-CoV-2 antigens across common HLA haplotypes
Most COVID-19 vaccines elicit immunity against the SARS-CoV-2 Spike protein. However, Spike protein mutations in emerging strains and immune evasion by the SARS-CoV-2 virus demonstrates the need to develop more broadly targeting vaccines. To facilitate this, we use mass spectrometry to identify immunopeptides derived from seven relatively conserved structural and non-structural SARS-CoV-2 proteins (N, E, Nsp1/4/5/8/9). We use two different B-lymphoblastoid cell lines to map Human Leukocyte Antigen (HLA) class I and class II immunopeptidomes covering some of the prevalent HLA types across the global human population. We employ DNA plasmid transfection and direct antigen delivery approaches to sample different antigens and find 248 unique HLA class I and HLA class II bound peptides with 71 derived from N, 12 from E, 28 from Nsp1, 19 from Nsp4, 73 from Nsp8 and 45 peptides derived from Nsp9. Over half of the viral peptides are unpublished. T cell reactivity tested against 56 of the detected peptides shows CD8
+
and CD4
+
T cell responses against several peptides from the N, E, and Nsp9 proteins. Results from this study will aid the development of next-generation COVID vaccines targeting epitopes from across a number of SARS-CoV-2 proteins.
The immune response to the spike protein of SARS-CoV-2 has been relatively well studied, but less is known about other viral proteins. Here, the authors identify immunopeptides from seven structural and non-structural SARS-CoV-2 proteins presented to the immune system by HLA molecules and confirm T-cell responses against some of them in convalescent individuals.
Journal Article
Epitope-anchored contrastive transfer learning for paired CD8+ T cell receptor–antigen recognition
Understanding the mechanisms of T cell antigen recognition that underpin adaptive immune responses is critical for developing vaccines, immunotherapies and treatments against autoimmune diseases. Despite extensive research efforts, accurate prediction of T cell receptor (TCR)–antigen binding pairs remains a great challenge due to the vast diversity and cross-reactivity of TCRs. Here we propose a deep-learning-based framework termed epitope-anchored contrastive transfer learning (EPACT) tailored to paired human CD8
+
TCRs. Harnessing the pretrained representations and co-embeddings of peptide–major histocompatibility complex (pMHC) and TCR, EPACT demonstrated generalizability in predicting binding specificity for unseen epitopes and distinct TCR repertoires. Contrastive learning enabled highly precise predictions for immunodominant epitopes and interpretable analysis of epitope-specific T cells. We applied EPACT to SARS-CoV-2-responsive T cells, and the predicted binding strength aligned well with the surge in spike-specific immune responses after vaccination. We further fine-tuned EPACT on structural data to decipher the residue-level interactions involved in TCR–antigen recognition. EPACT was capable of quantifying interchain distance matrices and identifying contact residues, corroborating the presence of TCR cross-reactivity across multiple tumour-associated antigens. Together, EPACT can serve as a useful artificial intelligence approach with important potential in practical applications and contribute towards the development of TCR-based immunotherapies.
Accurate prediction of T cell receptor (TCR)–antigen recognition remains a challenge. Zhang et al. propose a contrastive transfer learning model to predict TCR–pMHC binding that enables interpretable analyses of epitope-specific T cells and can decipher residue-level interactions.
Journal Article
A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi
Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies. To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found. This workshop discussed the benefits and barriers to CHIM studies in Malawi. Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains. Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.
Journal Article
Cross-sectional observational study of epidemiology of COVID-19 and clinical outcomes of hospitalised patients in North West London during March and April 2020
ObjectiveThe aim of this paper is to describe evolution, epidemiology and clinical outcomes of COVID-19 in subjects tested at or admitted to hospitals in North West London.DesignObservational cohort study.SettingLondon North West Healthcare NHS Trust (LNWH).ParticipantsPatients tested and/or admitted for COVID-19 at LNWH during March and April 2020Main outcome measuresDescriptive and analytical epidemiology of demographic and clinical outcomes (intensive care unit (ICU) admission, mechanical ventilation and mortality) of those who tested positive for COVID-19.ResultsThe outbreak began in the first week of March 2020 and reached a peak by the end of March and first week of April. In the study period, 6183 tests were performed in on 4981 people. Of the 2086 laboratory confirmed COVID-19 cases, 1901 were admitted to hospital. Older age group, men and those of black or Asian minority ethnic (BAME) group were predominantly affected (p<0.05). These groups also had more severe infection resulting in ICU admission and need for mechanical ventilation (p<0.05). However, in a multivariate analysis, only increasing age was independently associated with increased risk of death (p<0.05). Mortality rate was 26.9% in hospitalised patients.ConclusionThe findings confirm that men, BAME and older population were most commonly and severely affected groups. Only older age was independently associated with mortality.
Journal Article