Imperial College London

DrStephanieAscough

Faculty of MedicineDepartment of Infectious Disease

Research Associate
 
 
 
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s.ascough

 
 
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8.N20Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

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Year
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26 results found

Marsall P, Fandrich M, Griesbaum J, Harries M, Lange B, RESPINOW Study Consortium, Ascough S, Dayananda P, Chiu C, Remppis J, Ganzenmueller T, Renk H, Strengert M, Schneiderhan-Marra N, Dulovic Aet al., 2024, Development and validation of a respiratory syncytial virus multiplex immunoassay, Infection: journal of infectious disease, ISSN: 0300-8126

PURPOSE: Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory disease in infants and adults. While vaccines and monoclonal therapeutic antibodies either are or will shortly become available, correlates of protection remain unclear. For this purpose, we developed an RSV multiplex immunoassay that analyses antibody titers toward the post-F, Nucleoprotein, and a diverse mix of G proteins. METHODS: A bead-based multiplex RSV immunoassay was developed, technically validated to standard FDA bioanalytical guidelines, and clinically validated using samples from human challenge studies. RSV antibody titers were then investigated in children aged under 2 and a population-based cohort. RESULTS: Technical and clinical validation showed outstanding performance, while methodological developments enabled identification of the subtype of previous infections through use of the diverse G proteins for approximately 50% of samples. As a proof of concept to show the suitability of the assay in serosurveillance studies, we then evaluated titer decay and age-dependent antibody responses within population cohorts. CONCLUSION: Overall, the developed assay shows robust performance, is scalable, provides additional information on infection subtype, and is therefore ideally suited to be used in future population cohort studies.

Journal article

Wagstaffe HR, Thwaites RS, Reynaldi A, Sidhu JK, McKendry R, Ascough S, Papargyris L, Collins AM, Xu J, Lemm N-M, Siggins MK, Chain BM, Killingley B, Kalinova M, Mann A, Catchpole A, Davenport MP, Openshaw PJM, Chiu Cet al., 2024, Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults, Science Immunology, Vol: 9, ISSN: 2470-9468

Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling the identification of factors that are important for viral clearance. Here, we performed intranasal inoculation of 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected and showed an interferon-dominated mediator response with divergent kinetics between nasal and systemic sites. Peripheral CD4+ and CD8+ T cell activation and proliferation were early and robust but showed distinct kinetic and phenotypic profiles; antigen-specific T cells were largely CD38+Ki67+ and displayed central and effector memory phenotypes. Both mucosal and systemic antibodies became detectable around day 10, but nasal antibodies plateaued after day 14 while circulating antibodies continued to rise. Intensively granular measurements in nasal mucosa and blood allowed modeling of immune responses to primary SARS-CoV-2 infection that revealed CD8+ T cell responses and early mucosal IgA responses strongly associated with viral control, indicating that these mechanisms should be targeted for transmission-reducing intervention.

Journal article

Barnes MVC, Mandla A, Smith E, Maskuniitty M, Openshaw PJM, HIC-Vac meeting contributorset al., 2023, Human infection challenge in the pandemic era and beyond, HIC-Vac annual meeting report, 2022, Immunotherapy Advances, Vol: 3, ISSN: 2732-4303

HIC-Vac is an international network of researchers dedicated to developing human infection challenge studies to accelerate vaccine development against pathogens of high global impact. The HIC-Vac Annual Meeting (3rd and 4th November 2022) brought together stakeholders including researchers, ethicists, volunteers, policymakers, industry partners, and funders with a strong representation from low- and middle-income countries. The network enables sharing of research findings, especially in endemic regions. Discussions included pandemic preparedness and the role of human challenge to accelerate vaccine development during outbreak, with industry speakers emphasising the great utility of human challenge in vaccine development. Public consent, engagement, and participation in human challenge studies were addressed, along with the role of embedded social science and empirical studies to uncover social, ethical, and regulatory issues around human infection challenge studies. Study volunteers shared their experiences and motivations for participating in studies. This report summarises completed and ongoing human challenge studies across a variety of pathogens and demographics, and addresses other key issues discussed at the meeting.

Journal article

Ascough S, Ingram RJ, Chu KKY, Moore SJ, Gallagher T, Dyson H, Doganay M, Metan G, Ozkul Y, Baillie L, Williamson ED, Robinson JH, Maillere B, Boyton RJ, Altmann DMet al., 2022, Impact of HLA polymorphism on the immune response to bacillus anthracis protective antigen in vaccination versus natural infection, Vaccines, Vol: 10, Pages: 1-17, ISSN: 2076-393X

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.

Journal article

Ascough S, Dayananda P, Kalyan M, Kuong SU, Gardener Z, Bergstrom E, Paterson S, Kar S, Avadhan V, Thwaites R, Uruchurtu ASS, Ruckwardt TJ, Chen M, Nair D, Derrien-Colemyn A, Graham BS, Begg M, Hessel E, Openshaw P, Chiu Cet al., 2022, Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model, The Lancet Healthy Longevity, Vol: 3, Pages: E405-E416, ISSN: 2666-7568

BackgroundRespiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and accumulation of comorbidities. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological, and immunological outcomes.MethodsIn this human infection challenge pilot study, adults aged 18–55 years and 60–75 years were assessed for enrolment using protocol-defined inclusion and exclusion criteria. Symptoms were documented by self-completed diaries and viral load determined by quantitative PCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-fusion and post-fusion, NP, and G proteins in the blood and upper respiratory tract were measured. The study was registered with ClinicalTrials.gov, NCT03728413.Findings381 adults aged 60–75 years (older cohort) and 19 adults aged 18–55 years (young cohort) were assessed for enrolment using protocol-defined inclusion and exclusion criteria between Nov 12, 2018, and Feb 26, 2020. 12 healthy volunteers aged 60–75 years and 21 aged 18–55 years were inoculated intranasally with RSV Memphis-37. Nine (67%) of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without serious adverse events or sequelae. Viral load peaked on day 6 post-inoculation and symptoms peaked between days 6 and 8. Increases in circulating IgG-positive and IgA-positive antigen-specific plasmablasts, serum

Journal article

Paterson S, Kar S, Ung SK, Gardener Z, Bergstrom E, Ascough S, Kalyan M, Zyla J, Maertzdorf J, Mollenkopf H-J, Weiner J, Jozwik A, Jarvis H, Jha A, Nicholson BP, Veldman T, Woods CW, Mallia P, Kon OM, Kaufmann SHE, Openshaw PJ, Chiu Cet al., 2021, Innate-like gene expression of lung-resident memory CD8+ T-cells during experimental human influenza, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 826-841, ISSN: 1073-449X

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T cells recognizing peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection.Objectives: To investigate the kinetics, phenotypes, and function of influenza virus–specific CD8+ resident memory T (Trm) cells in the lower airway and infer the molecular pathways associated with their response to infection in vivo.Methods: Healthy volunteers, aged 18–55, were inoculated intranasally with influenza A/California/4/09(H1N1). Blood, upper airway, and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed by using self-reported diaries, and the nasal viral load was assessed by using quantitative PCR. T-cell responses were analyzed by using a three-color FluoroSpot assay, flow cytometry with MHC I–peptide tetramers, and RNA sequencing, with candidate markers being confirmed by using the immunohistochemistry results for endobronchial biopsy specimens.Measurements and Main Results: After challenge, 57% of participants became infected. Preexisting influenza-specific CD8+ T cells in blood correlated strongly with a reduced viral load, which peaked at Day 3. Influenza-specific CD8+ T cells in BAL fluid were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between preinfection CD8+ T cells in BAL fluid and blood by using RNA sequencing revealed 3,928 differentially expressed genes, including all major Trm-cell markers. However, gene set enrichment analysis of BAL-fluid CD8+ T cells showed primarily innate cell–related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10, and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues.Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blur

Journal article

Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, Fairfield C, Carter E, Abrams S, Short C, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty AB, Hunt D, Crow YJ, Solomon T, Taylor GP, Turtle L, Harrison EM, Dunning J, Semple MG, Baillie JK, Openshaw PJMet al., 2021, Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19, Science Immunology, Vol: 6, Pages: 1-17, ISSN: 2470-9468

While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

Journal article

Thwaites R, Sevilla Uruchurtu AS, Siggins M, Liew F, Russell C, Moore S, Carter E, Abrams S, Short C-E, Thaventhiran T, Bergstrom E, Gardener Z, Ascough S, Chiu C, Docherty A, Hunt D, Crow Y, Solomon T, Taylor G, Turtle L, Harrison E, Semple M, Baillie K, Openshaw PJMet al., 2020, Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19, Publisher: medRxiv

Introductory paragraph</h4> The mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical ‘cytokine storms’. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.

Working paper

Guvenel A, Jozwik A, Ascough S, Ung SK, Paterson S, Kalyan M, Bergstrom E, Kar S, Habibi MS, Paras A, Zhu J, Park M, Dhariwal J, Almond M, Wong EHC, Sykes A, Del Rosario J, Trujillo-Torralbo M, Mallia P, Sidney J, Peters B, Kon OM, Sette A, Johnston SL, Openshaw PJ, Chiu Cet al., 2020, Epitope-specific airway-resident CD4+ T-cell dynamics during experimental human RSV infection, Journal of Clinical Investigation, Vol: 130, Pages: 523-538, ISSN: 0021-9738

Background: Respiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T-cells play a key role in antiviral immunity, but they have been little studied in the human lung. Methods: Healthy adult volunteers were inoculated intranasally with RSV A Memphis 37. CD4+ T-cells in blood and lower airway were analysed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding. Results: Activated CD4+ T-cell frequencies in bronchoalveolar lavage correlated strongly with local CXCL10 levels. Thirty-nine epitopes were identified, predominantly towards the 3’ end of the viral genome. Five novel MHC-II tetramers were made using an immunodominant F-EFY epitope restricted to HLA-DR4, -DR9 and -DR11 (combined allelic frequency: 15% in Europeans) and G- DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labelling revealed enrichment of resident memory CD4+ T-cells (TRM) cells in the lower airway; these TRM displayed progressive differentiation, down-regulation of co- stimulatory molecules and elevated CXCR3 expression as infection evolved. Conclusion: Human infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of TRM recognising novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.

Journal article

Ascough S, Ingram RJ, Chu KKY, Moore SJ, Gallagher T, Dyson H, Doganay M, Metan G, Ozkul Y, Baillie L, Williamson ED, Robinson JH, Maillere B, Boyton RJ, Altmann DMet al., 2019, HLA class II polymorphism influences the immune response to protective antigen and susceptibility to <i>Bacillus anthracis</i>

<jats:title>Abstract</jats:title><jats:p>The causative agent of anthrax, <jats:italic>Bacillus anthracis</jats:italic>, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination will be vital in planning protective strategies against anthrax.</jats:p><jats:sec><jats:title>Author Summary</jats:title><jats:p>The bacterium responsible for causing the disease anthrax, Bacillus anthracis, produces a binary toxin composed of Protective Antigen (PA) and either Lethal Factor (LF) or Edema Factor (EF). Previous vaccination strategies have focused upon the antibody response to the PA subunit. Howev

Journal article

Ascough S, Vlachantoni I, Kalyan M, Haijema B-J, Wallin-Weber S, Dijkstra-Tiekstra M, Ahmed MS, van Roosmalen M, Grimaldi R, Zhang Q, Leenhouts K, Openshaw PJ, Chiu Cet al., 2019, Local and systemic immunity against RSV induced by a novel intranasal vaccine: A randomised, double- blind, placebo-controlled trial, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 481-492, ISSN: 1073-449X

RATIONALE: Needle-free intranasal vaccines offer major potential advantages, especially against pathogens entering via mucosal surfaces. As yet, there is no effective vaccine against respiratory syncytial virus (RSV), a ubiquitous pathogen of global importance that preferentially infects respiratory epithelial cells; new strategies are urgently required. OBJECTIVES: Here, we report the safety and immunogenicity of a novel mucosal RSV F protein vaccine linked to an immunostimulatory bacterium-like particle (BLP). METHODS: In this phase I, randomised, double-blind placebo-controlled trial, 48 healthy volunteers aged 18-49 years were randomly assigned to receive placebo or SynGEM (low- or high-dose) intranasally by prime-boost administration. The primary outcome was safety and tolerability, with secondary objectives assessing virus-specific immunogenicity. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in adverse events between placebo and vaccinated groups. SynGEM induced systemic plasmablast responses and significant, durable increases in RSV-specific serum antibody in healthy seropositive adults. Volunteers given low-dose SynGEM (140 µg F, 2mg BLP) required a boost at day 28 to achieve plateau responses with a maximum fold-change of 2.4, whereas high-dose recipients (350 µg F, 5mg BLP) achieved plateau responses with a fold-change of 1.5 after first vaccination that remained elevated up to 180 days post-vaccination irrespective of further boosting. Palivizumab-like antibodies were consistently induced, but F protein site Ø-specific antibodies were not detected and virus-specific nasal IgA responses were heterogeneous, with strongest responses in individuals with lower pre-existing antibody levels. CONCLUSIONS: SynGEM is thus the first non-replicating intranasal RSV subunit vaccine to induce persistent antibody responses in human volunteers. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02958540.

Journal article

Ascough SC, Paterson S, Chiu C, 2018, Induction and subversion of human protective immunity: contrasting influenza and respiratory syncytial virus, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

Respiratory syncytial virus (RSV) and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies) that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell generation and funct

Journal article

Ruiz-Hernandez R, Mwangi W, Peroval M, Sadeyen J-R, Ascough S, Balkissoon D, Staines K, Boyd A, McCauley J, Smith A, Butter Cet al., 2016, Host genetics determine susceptibility to avian influenza infection and transmission dynamics, Scientific Reports, Vol: 6, ISSN: 2045-2322

Host-genetic control of influenza virus infection has been the object of little attention. In this study we determined that two inbred lines of chicken differing in their genetic background , Lines 0 and C-B12, were respectively relatively resistant and susceptible to infection with the low pathogenicity influenza virus A/Turkey/England/647/77 as defined by substantial differences in viral shedding trajectories. Resistant birds, although infected, were unable to transmit virus to contact birds, as ultimately only the presence of a sustained cloacal shedding (and not oropharyngeal shedding) was critical for transmission. Restriction of within-bird transmission of virus occurred in the resistant line, with intra-nares or cloacal infection resulting in only local shedding and failing to transmit fully through the gastro-intestinal-pulmonary tract. Resistance to infection was independent of adaptive immune responses, including the expansion of specific IFNγ secreting cells or production of influenza-specific antibody. Genetic resistance to a novel H9N2 virus was less robust, though significant differences between host genotypes were still clearly evident. The existence of host-genetic determination of the outcome of influenza infection offers tools for the further dissection of this regulation and also for understanding the mechanisms of influenza transmission within and between birds.

Journal article

Ascough S, Ingram RJ, Chu KK, Musson JA, Moore SJ, Gallagher T, Baillie L, Williamson ED, Robinson JH, Maillere B, Boyton RJ, Altmann DMet al., 2016, CD4+ T Cells Targeting Dominant and Cryptic Epitopes from Bacillus anthracis Lethal Factor., Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X

Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called 'cryptic' or 'subdominant' epitopes. We analyzed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISpot assays we characterized epitopes that elicited a response following immunization with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, as a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 transgenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were influenced by the speci

Journal article

Ascough S, Altmann DM, 2015, Anthrax in injecting drug users: the need for increased vigilance in the clinic, EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, Vol: 13, Pages: 681-684, ISSN: 1478-7210

Journal article

Ingram RJ, Ascough S, Reynolds CJ, Metan G, Doganay M, Baillie L, Williamson DE, Robinson JH, Maillere B, Boyton RJ, Altmann DMet al., 2015, Natural cutaneous anthrax infection, but not vaccination, induces a CD4(+) T cell response involving diverse cytokines., Cell and Bioscience, Vol: 5, ISSN: 2045-3701

BACKGROUND: Whilst there have been a number of insights into the subsets of CD4(+) T cells induced by pathogenic Bacillus anthracis infections in animal models, how these findings relate to responses generated in naturally infected and vaccinated humans has yet to be fully established. We describe the cytokine profile produced in response to T cell stimulation with a previously defined immunodominant antigen of anthrax, lethal factor (LF), domain IV, in cohorts of individuals with a history of cutaneous anthrax, compared with vaccinees receiving the U.K. licenced Anthrax Vaccine Precipitated (AVP) vaccine. FINDINGS: We found that immunity following natural cutaneous infection was significantly different from that seen after vaccination. AVP vaccination was found to result in a polarized IFNγ CD4+ T cell response, while the individuals exposed to B. anthracis by natural infection mounted a broader cytokine response encompassing IFNγ, IL-5, -9, -10, -13, -17, and -22. CONCLUSIONS: Vaccines seeking to incorporate the robust, long-lasting, CD4 T cell immune responses observed in naturally acquired cutaneous anthrax cases may need to elicit a similarly broad spectrum cellular immune response.

Journal article

Ascough S, Ingram RJ, Chu KK, Reynolds CJ, Musson JA, Doganay M, Metan G, Ozkul Y, Baillie L, Sriskandan S, Moore SJ, Gallagher TB, Dyson H, Williamson ED, Robinson JH, Maillere B, Boyton RJ, Altmann DMet al., 2014, Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4<SUP>+</SUP> T Cell Immunity, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366

Journal article

Ascough S, Ingram R, Abarra A, Holmes A, Maillere B, Altmann A, Boyton Ret al., 2013, Injectional anthrax infection due to heroin use induces strong immunological memory, J Infect

Journal article

Lowther DE, Chong DL, Ascough S, Ettorre A, Ingram RJ, Boyton RJ, Altmann DMet al., 2013, Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response, ACTA NEUROPATHOLOGICA, Vol: 126, Pages: 501-515, ISSN: 0001-6322

Journal article

Ingram RJ, Harris A, Ascough S, Metan G, Doganay M, Ballie L, Williamson ED, Dyson H, Robinson JH, Sriskandan S, Altmann DMet al., 2013, Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 173, Pages: 84-91, ISSN: 0009-9104

Journal article

Ascough S, Ingram RJ, Altmann DM, 2012, Anthrax Lethal Toxin and the Induction of CD4 T Cell Immunity, TOXINS, Vol: 4, Pages: 878-899

Journal article

Ascough S, Ingram RJ, Metan G, Maillere B, Doganay M, Ozkul Y, Kim LU, Ballie L, Moore S, Huwar TB, Sriskandan S, Altmann DMet al., 2012, Comment on "Frequency of Epitope-Specific Naive CD4<SUP>+</SUP> T Cells Correlates with Immunodominance in the Human Memory Repertoire", JOURNAL OF IMMUNOLOGY, Vol: 188, Pages: 5205-5206, ISSN: 0022-1767

Journal article

Musson JA, Ingram R, Durand G, Ascough S, Waters EL, Hartley MG, Robson T, Maillere B, Williamson ED, Sriskandan S, Altmann D, Robinson JHet al., 2010, Repertoire of HLA-DR1-Restricted CD4 T-Cell Responses to Capsular Caf1 Antigen of <i>Yersinia pestis</i> in Human Leukocyte Antigen Transgenic Mice, INFECTION AND IMMUNITY, Vol: 78, Pages: 4356-4362, ISSN: 0019-9567

Journal article

Ingram RJ, Chu KK, Metan G, Maillere B, Doganay M, Ozkul Y, Dyson H, Williamson ED, Baillie L, Kim LU, Ascough S, Sriskandan S, Altmann DMet al., 2010, An Epitope of <i>Bacillus anthracis</i> Protective Antigen That Is Cryptic in Rabbits May Be Immunodominant in Humans, INFECTION AND IMMUNITY, Vol: 78, Pages: 2353-2353, ISSN: 0019-9567

Journal article

Ingram RJ, Metan G, Maillere B, Doganay M, Ozkul Y, Kim LU, Baillie L, Dyson H, Williamson ED, Chu KK, Ascough S, Moore S, Huwar TB, Robinson JH, Sriskandan S, Altmann DMet al., 2010, Natural Exposure to Cutaneous Anthrax Gives Long-Lasting T Cell Immunity Encompassing Infection-Specific Epitopes, JOURNAL OF IMMUNOLOGY, Vol: 184, Pages: 3814-3821, ISSN: 0022-1767

Journal article

Kaushansky N, Altmann DA, Ascough S, David CS, Lassmann H, Ben-Nun Aet al., 2009, HLA-DQB1*0602 Determines Disease Susceptibility in a New "Humanized" Multiple Sclerosis Model in HLA-DR15 (DRB1*1501;DQB1*0602) Transgenic Mice, JOURNAL OF IMMUNOLOGY, Vol: 183, Pages: 3531-3541, ISSN: 0022-1767

Journal article

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