Imperial College London

Dr John S Tregoning

Faculty of MedicineDepartment of Infectious Disease

Reader in Respiratory Infections
 
 
 
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Contact

 

john.tregoning Website

 
 
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Location

 

456 (Shattock Group)Wright Fleming WingSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

100 results found

Cole ME, Kundu R, Abdulla AF, Andrews N, Hoschler K, Southern J, Jackson D, Miller E, Zambon M, Turner PJ, Tregoning JSet al., 2020, Pre-existing influenza specific nasal IgA or nasal viral infection does not affect live attenuated influenza vaccine immunogenicity in children., Clinical and Experimental Immunology, ISSN: 0009-9104

The United Kingdom has a national immunisation program which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Since LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal IgA in children aged 6-14 years. Nasopharyngeal swabs were collected prior to LAIV immunisation, to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21-28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing dataset of LAIV shedding from the same individuals, measured by RT-PCR. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact on whether vaccine virus RNA was detectable after immunisation. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunisation. Overall, we observed no effect of pre-existing influenza specific nasal antibody levels on immunogenicity, supporting annual immunisation with LAIV in children.

Journal article

Tregoning JS, 2020, First human efficacy study of a plant-derived influenza vaccine, LANCET, Vol: 396, Pages: 1464-1465, ISSN: 0140-6736

Journal article

Tregoning JS, Brown ES, Cheeseman HM, Flight KE, Higham SL, Lemm N-M, Pierce BF, Stirling DC, Wang Z, Pollock KMet al., 2020, Vaccines for COVID-19, Clinical and Experimental Immunology, Vol: 202, Pages: 162-192, ISSN: 0009-9104

Since the emergence of COVID-19, caused by the SARS-CoV-2 virus, at the end of 2019 there has been an explosion of vaccine development. By the 1st September 2020, a staggering number of vaccines (over 200) had started pre-clinical development of which 39 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socialising. Importantly, to effectively control the COVID-19 pandemic, production needs to be scaled up from a small number of pre-clinical doses to enough filled vials to immunise the world's population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS-CoV-2 and the potential for vaccine-induced immunopathology. It describes the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising pre-clinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began, we are at a point where pre-clinical and early clinical data is being generated for the vaccines, an overview of this important area will help our understanding of the next phases.

Journal article

Tregoning J, 2020, Coronavirus diaries: a new year for science., Nature

Journal article

Tregoning J, 2020, Coronavirus diaries: give your brain a break from science busywork, it deserves it., NATURE, Vol: 585, Pages: 471-472, ISSN: 0028-0836

Journal article

Tregoning J, Busse D, Kaforou M, Levin M, Herberg J, Kellam P, Bassano Iet al., 2020, Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus, Journal of Virology, Vol: 94, Pages: 1-15, ISSN: 0022-538X

Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defence. We have previously used a bioinformatic screen to identify two interferon stimulated genes (ISG) with poorly characterised function, Interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in Respiratory Syncytial Virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model we investigated the antiviral capability of these genes in the control of RSV replication. Over-expression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time post infection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection.

Journal article

Tregoning J, 2020, Coronavirus diaries: social media in an unsocial age, Nature, ISSN: 0028-0836

Journal article

Tregoning J, 2020, Coronavirus diaries: taking leave, but not holiday., Nature

Journal article

Tregoning J, 2020, Coronavirus diaries: We'll meet again., Nature, ISSN: 0028-0836

Journal article

Tregoning J, 2020, Coronavirus diaries: all the things we do not do., Nature

Journal article

Tregoning J, 2020, Coronavirus diaries: school's out forever., Nature, Vol: 581, Pages: 226-227

Journal article

Tregoning J, 2020, Coronavirus diaries: creature comforts., Nature, Vol: 581, Pages: 227-227

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Tregoning J, 2020, Coronavirus diaries: to be a scientist., Nature, ISSN: 0028-0836

Journal article

Tregoning J, 2020, Coronavirus diaries: hello from home., Nature, ISSN: 0028-0836

Journal article

Tregoning J, Weiner J, Cizmeci D, Hake D, Maertzdorf J, Kaufmann SHE, Leroux-Roels G, Maes C, Aerssens A, Calvert A, Jones CEet al., 2020, Pregnancy has a minimal impact on the acute transcriptional signature to vaccination, npj Vaccines, Vol: 5, ISSN: 2059-0105

Vaccination in pregnancy is an effective tool to protect both the mother and infant; vaccines against influenza, pertussis and tetanus are currently recommended. A number of vaccines with a specific indication for use in pregnancy are in development, with the specific aim of providing passive humoral immunity to the newborn child against pathogens responsible for morbidity and mortality in young infants. However, the current understanding about the immune response to vaccination in pregnancy is incomplete. We analysed the effect of pregnancy on early transcriptional responses to vaccination. This type of systems vaccinology approach identifies genes and pathways that are altered in response to vaccination and can be used to understand both the acute inflammation in response to the vaccine and to predict immunogenicity. Pregnant women and mice were immunised with Boostrix-IPV, a multivalent vaccine, which contains three pertussis antigens. Blood was collected from women before and after vaccination and RNA extracted for analysis by microarray. While there were baseline differences between pregnant and non-pregnant women, vaccination induced characteristic patterns of gene expression, with upregulation in interferon response and innate immunity gene modules, independent of pregnancy. We saw similar patterns of responses in both women and mice, supporting the use of mice for preclinical screening of novel maternal vaccines. Using a systems vaccinology approach in pregnancy demonstrated that pregnancy does not affect the initial response to vaccination and that studies in non-pregnant women can provide information about vaccine immunogenicity and potentially safety.

Journal article

Tregoning JS, McDermott JE, 2020, Ten simple rules to becoming a principal investigator, PLoS Computational Biology, Vol: 16, ISSN: 1553-734X

The biggest choke point in an academic career is going from postdoc to principal investigator (PI): moving from doing someone else’s research to getting other people to do yours. Being a PI is a fundamentally different job to being a postdoc; they just happen to be in the same environment. It is not an easy transition. It draws on few of the skills you learn at the bench, and the odds are clearly not ever in your favor. So, calling this article Ten Simple Rules is obviously a simplification. It is more accurate to call them ten tricky steps.In this article, we use PI to mean anyone who runs their own research group using funding that they have been awarded to answer their own questions. PI encompasses a number of different job titles depending on where the research is performed: fellow, lecturer, reader, associate professor, and senior scientist. One test is whether you can describe the people working for you as the X group, in which X is your surname. The normal route from undergraduate to lab head involves a PhD, one or more postdoc positions, and then PI. Given the diversity of ways to be a PI, the final step up from postdoc takes a number of forms. In the United Kingdom, this tends to be either an individual fellowship or a lecturer position, and in the United States, it generally starts with an independent position with associated funding—either as a start-up package or funded grant.The aim of this article is to identify some of the broader skills (rules 1–4) and behaviors (rules 5–10) that can help with getting a PI position. It is meant as advice not instruction. As you will see, we are advocating the development of social intelligence, which is as useful in the world outside academia as within it.

Journal article

Groves HT, Higham SL, Moffatt MF, Cox MJ, Tregoning JSet al., 2020, Respiratory viral infection alters the gut microbiota by inducing inappetence, mBio, Vol: 11, ISSN: 2150-7511

Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined.

Journal article

Mooney JP, Qendro T, Keith M, Philbey AW, Groves HT, Tregoning JS, Goodier MR, Riley EMet al., 2020, Natural Killer cells dampen the pathogenic features of recall responses to influenza infection, Frontiers in Immunology, Vol: 11, Pages: 1-14, ISSN: 1664-3224

Despite evidence of augmented Natural Killer (NK) cell responses after influenza vaccination, the role of these cells in vaccine-induced immunity remains unclear. Here, we hypothesized that NK cells might increase viral clearance but possibly at the expense of increased severity of pathology. On the contrary, we found that NK cells serve a homeostatic role during influenza virus infection of vaccinated mice, allowing viral clearance with minimal pathology. Using a diphtheria toxin receptor transgenic mouse model, we were able to specifically deplete NKp46+ NK cells through the administration of diphtheria toxin. Using this model, we assessed the effect of NK cell depletion prior to influenza challenge in vaccinated and unvaccinated mice. NK-depleted, vaccinated animals lost significantly more weight after viral challenge than vaccinated NK intact animals, indicating that NK cells ameliorate disease in vaccinated animals. However, there was also a significant reduction in viral load in NK-depleted, unvaccinated animals indicating that NK cells also constrain viral clearance. Depletion of NK cells after vaccination, but 21 days before infection, did not affect viral clearance or weight loss—indicating that it is the presence of NK cells during the infection itself that promotes homeostasis. Further work is needed to identify the mechanism(s) by which NK cells regulate adaptive immunity in influenza-vaccinated animals to allow efficient and effective virus control whilst simultaneously minimizing inflammation and pathology.

Journal article

Shelkovnikova TA, An H, Skelt L, Tregoning JS, Humphreys IR, Buchman VLet al., 2019, Antiviral immune response as a trigger of FUS proteinopathy in amyotrophic lateral sclerosis, Cell Reports, Vol: 29, Pages: 4496-4508.E4, ISSN: 2211-1247

Mutations in the FUS gene cause familial amyotrophic lateral sclerosis (ALS-FUS). In ALS-FUS, FUS-positive inclusions are detected in the cytoplasm of neurons and glia, a condition known as FUS proteinopathy. Mutant FUS incorporates into stress granules (SGs) and can spontaneously form cytoplasmic RNA granules in cultured cells. However, it is unclear what can trigger the persistence of mutant FUS assemblies and lead to inclusion formation. Using CRISPR/Cas9 cell lines and patient fibroblasts, we find that the viral mimic dsRNA poly(I:C) or a SG-inducing virus causes the sustained presence of mutant FUS assemblies. These assemblies sequester the autophagy receptor optineurin and nucleocytoplasmic transport factors. Furthermore, an integral component of the antiviral immune response, type I interferon, promotes FUS protein accumulation by increasing FUS mRNA stability. Finally, mutant FUS-expressing cells are hypersensitive to dsRNA toxicity. Our data suggest that the antiviral immune response is a plausible second hit for FUS proteinopathy.

Journal article

Mooney JP, Qendro T, Keith M, Philbey AW, Groves HT, Tregoning JS, Goodier MR, Riley EMet al., 2019, Natural Killer cells dampen the pathogenic features of recall responses to influenza infection, Publisher: bioRxiv

Despite evidence of augmented Natural Killer (NK) cell responses after influenza vaccination, the role of these cells in vaccine-induced immunity remains unclear. Here, we hypothesized that NK cells might increase viral clearance but possibly at the expense of increased severity of pathology. On the contrary, we found that NK cells serve a homeostatic role during influenza virus infection of vaccinated mice, allowing viral clearance with minimal pathology. Using a diphtheria toxin receptor transgenic mouse model, we were able to specifically deplete NKp46+ NK cells through the administration of diphtheria toxin. Using this model, we assessed the effect of NK cell depletion prior to influenza challenge in vaccinated and unvaccinated mice. NK-depleted, vaccinated animals lost significantly more weight after viral challenge than vaccinated NK intact animals, indicating that NK cells ameliorate disease in vaccinated animals. However, there was also a significant reduction in viral load in NK-depleted, unvaccinated animals indicating that NK cells also constrain viral clearance. Depletion of NK cells after vaccination, but 21 days before infection, did not affect viral clearance or weight loss - indicating that it is the presence of NK cells during the infection itself that promotes homeostasis. Further work is needed to identify the mechanism(s) by which NK cells regulate adaptive immunity in influenza-vaccinated animals to allow efficient and effective virus control whilst simultaneously minimizing inflammation and pathology.

Working paper

Jawinski K, Hartmann M, Singh C, Kinnear E, Busse DC, Ciabattini A, Fiorino F, Medaglini D, Trombetta CM, Montomoli E, Contreras V, Le Grand R, Coiffier C, Primard C, Verrier B, Tregoning JSet al., 2019, Recombinant haemagglutinin derived from the ciliated protozoan tetrahymena thermophila Is protective against influenza infection, Frontiers in Immunology, Vol: 10, Pages: 1-14, ISSN: 1664-3224

Current influenza vaccines manufactured using eggs have considerable limitations, both in terms of scale up production and the potential impact passaging through eggs can have on the antigenicity of the vaccine virus strains. Alternative methods of manufacture are required, particularly in the context of an emerging pandemic strain. Here we explore the production of recombinant influenza haemagglutinin using the ciliated protozoan Tetrahymena thermophila. For the first time we were able to produce haemagglutinin from both seasonal influenza A and B strains. This ciliate derived material was immunogenic, inducing an antibody response in both mice and non-human primates. Mice immunized with ciliate derived haemagglutinin were protected against challenge with homologous influenza A or B viruses. The antigen could also be combined with submicron particles containing a Nod2 ligand, significantly boosting the immune response and reducing the dose of antigen required. Thus, we show that Tetrahymena can be used as a manufacturing platform for viral vaccine antigens.

Journal article

Turner P, Abdulla AF, Cole M, Javan RR, Gould V, O'Driscoll ME, Southern J, Zambon M, Miller E, Andrews NJ, Hoschler K, Tregoning Jet al., 2019, Differences in nasal IgA responses to influenza vaccine strains after Live Attenuated Influenza Vaccine (LAIV) immunisation in children, Clinical and Experimental Immunology, Vol: 199, Pages: 109-118, ISSN: 0009-9104

Different vaccine strains included in the Live Attenuated Influenza Vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a phase IV open‐label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunisation. There was a significant increase in nasal IgA to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting the response is multi‐factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine, the reasons for this require further investigation.

Journal article

Poux C, Dondalska A, Bergenstrahle J, Palsson S, Contreras V, Arasa C, Jarver P, Albert J, Busse DC, LeGrand R, Lundeberg J, Tregoning JS, Spetz A-Let al., 2019, A single-stranded oligonucleotide inhibits toll-like receptor 3 activation and reduces influenza A (H1N1) infection, Frontiers in Immunology, Vol: 10, Pages: 1-16, ISSN: 1664-3224

The initiation of an immune response is dependent on the activation and maturation of dendritic cells after sensing pathogen associated molecular patterns by pattern recognition receptors. However, the response needs to be balanced as excessive pro-inflammatory cytokine production in response to viral or stress-induced pattern recognition receptor signaling has been associated with severe influenza A virus (IAV) infection. Here, we use an inhibitor of Toll-like receptor (TLR)3, a single-stranded oligonucleotide (ssON) with the capacity to inhibit certain endocytic routes, or a TLR3 agonist (synthetic double-stranded RNA PolyI:C), to evaluate modulation of innate responses during H1N1 IAV infection. Since IAV utilizes cellular endocytic machinery for viral entry, we also assessed ssON's capacity to affect IAV infection. We first show that IAV infected human monocyte-derived dendritic cells (MoDC) were unable to up-regulate the co-stimulatory molecules CD80 and CD86 required for T cell activation. Exogenous TLR3 stimulation did not overcome the IAV-mediated inhibition of co-stimulatory molecule expression in MoDC. However, TLR3 stimulation using PolyI:C led to an augmented pro-inflammatory cytokine response. We reveal that ssON effectively inhibited PolyI:C-mediated pro-inflammatory cytokine production in MoDC, notably, ssON treatment maintained an interferon response induced by IAV infection. Accordingly, RNAseq analyses revealed robust up-regulation of interferon-stimulated genes in IAV cultures treated with ssON. We next measured reduced IAV production in MoDC treated with ssON and found a length requirement for its anti-viral activity, which overlapped with its capacity to inhibit uptake of PolyI:C. Hence, in cases wherein an overreacting TLR3 activation contributes to IAV pathogenesis, ssON can reduce this signaling pathway. Furthermore, concomitant treatment with ssON and IAV infection in mice resulted in maintained weight and reduced viral load in the lungs. Th

Journal article

Lindsey BB, Jagne YJ, Armitage EP, Singanayagam A, Sallah HJ, Drammeh S, Senghore E, Mohammed NI, Jeffries D, Höschler K, Tregoning JS, Meijer A, Clarke E, Dong T, Barclay W, Kampmann B, de Silva TIet al., 2019, Effect of a Russian-backbone live-attenuated influenza vaccine with an updated pandemic H1N1 strain on shedding and immunogenicity among children in The Gambia: an open-label, observational, phase 4 study, Lancet Respiratory Medicine, Vol: 7, Pages: 665-676, ISSN: 2213-2600

BACKGROUND: The efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in live attenuated influenza vaccine (LAIV) is poor. The reasons for this paucity are unclear but could be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) strains. We assessed whether an updated pH1N1 strain in the Russian-backbone trivalent LAIV resulted in greater shedding and immunogenicity compared with LAIV with Cal09. METHODS: We did an open-label, prospective, observational, phase 4 study in Sukuta, a periurban area in The Gambia. We enrolled children aged 24-59 months who were clinically well. Children received one dose of the WHO prequalified Russian-backbone trivalent LAIV containing either A/17/California/2009/38 (Cal09) or A/17/New York/15/5364 (NY15) based on their year of enrolment. Primary outcomes were the percentage of children with LAIV strain shedding at day 2 and day 7, haemagglutinin inhibition seroconversion, and an increase in influenza haemagglutinin-specific IgA and T-cell responses at day 21 after LAIV. This study is nested within a randomised controlled trial investigating LAIV-microbiome interactions (NCT02972957). FINDINGS: Between Feb 8, 2017, and April 12, 2017, 118 children were enrolled and received one dose of the Cal09 LAIV from 2016-17. Between Jan 15, 2018, and March 28, 2018, a separate cohort of 135 children were enrolled and received one dose of the NY15 LAIV from 2017-18, of whom 126 children completed the study. Cal09 showed impaired pH1N1 nasopharyngeal shedding (16 of 118 children [14%, 95% CI 8·0-21·1] with shedding at day 2 after administration of LAIV) compared with H3N2 (54 of 118 [46%, 36·6-55·2]; p<0·0001) and influenza B (95 of 118 [81%, 72·2-87·2]; p<0·0001), along with suboptimal serum antibody (seroconversion in six of 118 [5%, 1·9-10·7]) and T-cell responses (CD4+ interferon γ-positive and/or CD4+ interleukin 2-positive

Journal article

Groves H, Higham S, Moffatt M, Cox M, Tregoning Jet al., 2019, Respiratory viral infection alters the gut microbiota by inducing inappetence, Publisher: bioRxiv

Abstract The gut microbiota has an important role in health and disease. Respiratory viral infections are extremely common but their impact on the composition and function of the gut microbiota is poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here we show that weight loss during Respiratory Syncytial Virus (RSV) or influenza virus infection was due to decreased food consumption, and that fasting mice independently of infection altered gut microbiota composition. While the acute phase TNF-α response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, depleting CD8 + cells increased food intake and prevented weight loss resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the faecal gut metabolome during RSV infection, with a significant shift in lipid metabolism. Sphingolipids, poly-unsaturated fatty acids (PUFAs) and the short-chain fatty acid (SCFA) valerate all increased in abundance in the faecal metabolome following RSV infection. Whether this, and the impact of infection-induced anorexia on the gut microbiota, are part of a protective, anti-inflammatory response during respiratory viral infections remains to be determined.

Working paper

Smith SE, Busse DC, Binter Š, Weston S, Diaz Soria C, Laksono BM, Clare S, Van Nieuwkoop S, Van den Hoogen BG, Clement M, Marsden M, Humphreys IR, Marsh M, de Swart RL, Wash RS, Tregoning JS, Kellam Pet al., 2019, Interferon-induced transmembrane protein 1 restricts replication of virus that enter cells via the plasma membrane, Journal of Virology, Vol: 93, ISSN: 1098-5514

The acute anti-viral response is mediated by a family of interferon stimulated genes (ISG), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with anti-viral function are the interferon-inducible transmembrane proteins (IFITM) of which IFITM3 has been studied extensively. By contrast, IFITM1 has not been studied in detail. Since IFITM1 can localise to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including Respiratory Syncytial Virus (RSV), mumps virus and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localisation for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localisation of the protein and reduced anti-viral activity. Screening published datasets, twelve rare non-synonymous SNPs were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1-/- knock-out mouse we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly anti-viral and this anti-viral function is associated with cell surface localisation.IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect o

Journal article

Lindsey BB, Singanayagam A, Tregoning JS, De Silva T, Barclay Wet al., 2019, The impact of an updated pandemic H1N1 strain on shedding and immunogenicity to Russian-backbone live attenuated influenza vaccine among children in The Gambia: an open-label, observational, phase 4 study, Lancet Respiratory Medicine, ISSN: 2213-2600

Background: Poor efficacy and effectiveness of thepandemic H1N1 (pH1N1) component inlive attenuated influenza vaccine (LAIV)has been demonstrated in several studies.The reasons for this are unclear, butmay be due toimpairedreplicative fitness of pH1N1 A/California/07/2009-like (Cal09) strains. The aim of this study was to establish whether an updated pH1N1 strain in the Russian-backbone trivalent LAIV resulted in greater shedding and immunogenicitycompared to Cal09.Methods: In an open-label, prospective,observational,phase 4study, we evaluated the impact of updating the pH1N1 component in the WHO prequalified Russian-backbone trivalent LAIV from Cal09in 2016-17(n=118) to an A/Michigan/45/2015-like strain (A/17/New York/15/5364, NY15) in 2017-18(n=126),on shedding and immunogenicity in Gambian children aged 2-4 years old.The study was nested within a randomised controlled trial investigating LAIV-microbiome interactions (ClinicalTrials.gov NCT02972957). Findings: Cal09 showed impairednasopharyngeal shedding(13.6%children shedding at day 2 post-LAIV)compared to H3N2(45.8%)and influenza B(80.5%), along with sub-optimal serum antibody(5.1%seroconversion)and T-cell responses(40.5% CD4+IFN-g+ and/or CD4+IL-2+responders). Following the switch to NY15, a significant increase in pH1N1 shedding(63.5%)was seen, along with improvements in seroconversion(19.1%)and influenza-specific CD4+ T-3cell responses(65.7%). The improvement in pH1N1 seroconversion with NY15 was even greater in children seronegative at baseline(37.5% vs. 7.6%). Persistent shedding today 7was independently associated with both seroconversionand CD4+ T cell responsein multivariable logistic regression. Interpretation:The pH1N1 component switch may have overcome problems in prior LAIV formulations.LAIV effectiveness against pH1N1 shouldtherefore improve in upcoming influenza seasons. Our dataalso highlightthe importance of evaluat

Journal article

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