Publications
187 results found
Adrielle Dos Santos L, Filho PGDG, Silva AMF, et al., 2021, Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers, Journal of Infection, Vol: 82, Pages: 399-406, ISSN: 0163-4453
BACKGROUND: There is growing concern about individuals reported to suffer repeat COVID-19 disease episodes, these in a small number of cases characterised as de novo infections with distinct sequences, indicative of insufficient protective immunity even in the short term. METHODS: Observational case series and case-control studies reporting 33 cases of recurrent, symptomatic, qRT-PCR positive COVID-19. Recurrent disease was defined as symptomatic recurrence after symptom-free clinical recovery, with release from isolation >14 days from the beginning of symptoms confirmed by qRT-PCR. The case control study-design compared this group of patients with a control group of 62 patients randomly selected from the same COVID-19 database. RESULTS: Of 33 recurrent COVID-19 patients, 26 were female and 30 were HCW. Mean time to recurrence was 50.5 days which was associated with being a HCW (OR 36.4 (p <0.0001)), and blood type A (OR 4.8 (p = 0.002)). SARS-CoV-2 antibodies were signifcantly lower in recurrent patients after initial COVID-19 (2.4 ± 0.610; p<0.0001) and after recurrence (6.4 ± 11.34; p = 0.007). Virus genome sequencing identified reinfection by a different isolate in one patient. CONCLUSIONS: This is the first detailed case series showing COVID-19 recurrence with qRT-PCR positivity. For one individual detection of phylogenetically distinct genomic sequences in the first and second episodes confirmed bona fide renfection, but in most cases the data do not formally distinguish between reinfection and re-emergence of a chronic infection reservoir. These episodes were significantly associated with reduced Ab response during initial disease and argue the need for ongoing vigilance without an assumption of protection after a first episode.
Altmann DM, Boyton RJ, 2021, Decoding the unknowns in long covid, BMJ: British Medical Journal, Vol: 372, Pages: 1-2, ISSN: 0959-535X
Boyton R, Pieper F, Altmann DM, 2021, Defense Systems, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 179-184, ISBN: 9780081027233
The lung is the anatomical site not only for gaseous exchange, but also for high-turnover sampling of pathogens and other antigenic and allergenic material. It constitutes a vast mucosal surface area, constantly exposed to inhaled substances that, allowed free ingress, would cause substantial damage or death. Any defense mechanism must accommodate the fact that the respiratory tract is made up of delicate tissues required for gas exchange. The lung, therefore, requires a multilayered system of protection that allows a fast, efficient, and effective response able to deal with infectious pathogens and other foreign particles without damaging the lung itself in the process. This encompasses physical barriers, innate immune mechanisms, and the cellular and antibody adaptive immune response. The price of excessive or inappropriate inflammatory responses can be high and may lead to lung damage. The first line of defense against entry to the lung is from physical barriers such as mucus and cilia, followed by the innate immune response that includes a battery of mediators such as lactoferrin, lysozyme, collectins, and defensins. Release of these molecules leads directly to lysis of pathogens, or destruction through opsonization or the recruitment of inflammatory cells. Rapid activation of the innate immune response also comes through the triggering of Toll-like receptors (TLRs) and the chemotactic recruitment and activation of neutrophils. Natural killer (NK) cells provide a fast and effective immune surveillance response against infectious pathogens. Type I interferons exert a direct antiviral effect. The adaptive immune response contributes by making neutralizing antibodies and T lymphocytes orchestrate antigen-specific immune responses through their ability to differentiate self from nonself and provide memory. T lymphocyte populations of different cytokine phenotypes—so-called T-helper-1 (Th1), T-helper-2 (Th2) and T-helper-17 (Th17)—dramatically alter the b
Boyton RJ, Murray S, Altmann DM, 2021, Notch, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 719-722, ISBN: 9780081027233
The Notch family of transmembrane receptors are a highly evolutionarily conserved set of molecules that interact with two key families of ligands, Delta and Serrate/Jagged, to perform a broad range of functions at switch points of cell fate determination. In mammals, there are four Notch receptors (Notch-1 through -4) and five ligands (Jagged-1 and -2 and Delta-1, -3, and -4). The ligand–receptor interaction leads to proteolytic cleavage of the receptor, liberating the cytoplasmic domain for translocation to the nucleus and interaction with transcription pathways. Signals transmitted through Notch affect differentiation, proliferation, cell-cycle arrest, border formation, and apoptosis at all stages of development, from embryonic development to cell fate decisions in differentiated cell lineages. As such, Notch signaling impinges on several body systems. Its effects in diverse biological systems are fundamental and wide reaching, and many of its functions are not yet determined. There are several areas under investigation, including the role of Notch in developmental biology and T-cell immunology, making it an exciting subject for current scientific debate where there are still many unknowns. Examples of the possible influences of Notch expression in the respiratory system include its effects on the development of lung tissue and on polarization of T-lymphocyte effector function in the immune system. In oncogenesis including lung cancer, Notch may act either as a tumor oncogene or as a tumor suppressor gene, depending on the specific cellular context.
Simonds AK, Boyton RJ, 2021, Vaccines: immunology, regulation and clinical management, ERS Monograph, Vol: 2021, Pages: 244-260, ISSN: 2312-508X
The pandemic has facilitated an explosion in the development of new platforms for vaccines and rapid regulatory approval systems. The COVID-19 vaccines have been produced in record time and have proved far more effective than expected. In many countries, the roll out of vaccination initially proved effective in reducing severe disease, but there are major concerns following the emergence of SARS-CoV-2 variants, especially omicron, where vaccine boosting is required to maximise effect. Vaccine hesitancy, the spread of disinformation and the equitable delivery of vaccines worldwide remain significant challenges.
Stowell JM, José RJ, Loebinger MR, et al., 2021, Bronchiectasis, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 266-279, ISBN: 9780081027233
Bronchiectasis is abnormal chronic dilatation of one or more bronchi due to loss of structural elements in the bronchial wall. There are a number of known causes and several associated conditions, but the underlying cause is not known in many cases. The prevalence is unknown, but thin-section computed tomography has increased its recognition. Symptoms are of chronic productive cough, breathlessness, recurrent exacerbations usually provoked by infection, and tiredness. There may be crackles over affected areas but not in all cases, and there may be wheezes due to airflow obstruction that is largely irreversible. Subsegmental airways are permanently dilated, tortuous, and contain excess secretions. Characteristically, the elastin layer of the wall is deficient, and muscle and cartilage show signs of destruction. Increased mucus production and impaired clearance predispose to bacterial infection, which stimulates chronic inflammation in which lymphocytes predominate within the wall and neutrophils in the lumen. The inflammation causes more damage, which in turn further impairs the lung defenses, leading to more infection and a vicious cycle of events. Treatment involves daily physiotherapy to drain affected areas and appropriate antibiotics to treat infection and thus reduce inflammation.
Reynolds CJ, Swadling L, Gibbons JM, et al., 2020, Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection., Science Immunology, Vol: 5, Pages: 1-19, ISSN: 2470-9468
Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.
Gregorova M, Morse D, Brignoli T, et al., 2020, Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia, eLife, Vol: 9, ISSN: 2050-084X
Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient's persistent symptoms and radiological changes.
Alcantara DR, Jones C, Altmann DM, et al., 2020, Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 114, Pages: 926-936, ISSN: 0035-9203
BackgroundPodoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease.MethodsNanoString technology was used to assess expression of 579 immune-related genes in formalin-fixed and paraffin-embedded lymph node archival samples from podoconiosis patients and unaffected controls.ResultsForty-eight genes were upregulated and 21 downregulated in podoconiosis samples compared with controls. Gene ontology analysis showed differentially expressed genes to be closely related to major histocompatibility complex protein, cytokine and TNF receptor binding genes. Pathway enrichment analysis revealed involvement of lymphocyte activation, adaptive immunity, cytokine signalling, antigen processing and the IL-12 pathways.ConclusionsThis exploratory study reports a multiplex gene expression analysis in podoconiosis and shows upregulation of pro-inflammatory transcripts compatible with the notion of local, chronic immune activation in this HLAII-associated disease. Implicated pathways will inform future research into podoconiosis immunopathogenesis.
Campbell VL, Nguyen L, Snoey E, et al., 2020, Proteome-wide Zika virus CD4 T cell epitope and HLA restriction determination, ImmunoHorizons, Vol: 4, Pages: 444-453, ISSN: 2573-7732
Zika virus (ZIKV) is a mosquito-borne pathogen that caused an epidemic in 2015-2016. ZIKV-specific T cell responses are functional in animal infection models, and helper CD4 T cells promote avid Abs in the vaccine context. The small volumes of blood available from field research limit the determination of T cell epitopes for complex microbes such as ZIKV. The goal of this project was efficient determination of human ZIKV CD4 T cell epitopes at the whole proteome scale, including validation of reactivity to whole pathogen, using small blood samples from convalescent time points when T cell response magnitude may have waned. Polyclonal enrichment of candidate ZIKV-specific CD4 T cells used cell-associated virus, documenting that T cells in downstream peptide analyses also recognize whole virus after Ag processing. Sequential query of bulk ZIKV-reactive CD4 T cells with pooled/single ZIKV peptides and molecularly defined APC allowed precision epitope and HLA restriction assignments across the ZIKV proteome and enabled discovery of numerous novel ZIKV CD4 T cell epitopes. The research workflow is useful for the study of emerging infectious diseases with a very limited human blood sample availability.
Altmann DM, Boyton RJ, 2020, SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection, Science Immunology, Vol: 5, ISSN: 2470-9468
In efforts to synthesize a clear understanding of SARS-CoV-2 protective immunity, antibody analysis has been paralleled by T cell studies across asymptomatic, mild and severe COVID-19. Defining CD4 and CD8 effector functions in protection is important considering that antibody responses appear short-lived and T cell memory is potentially more durable. To fully understand population level immunity, screening for both antibody and T cell immunity using standardized testing methods would be beneficial.
Altmann DM, Douek DC, Boyton RJ, 2020, What policy makers need to know about COVID-19 protective immunity, The Lancet, Vol: 395, Pages: 1527-1529, ISSN: 0140-6736
Stowell J, Reynolds C, Boyton R, 2020, The impact of mesenchymal stem cells on host immunity and disease outcome in bacterial lung infection., Clin Med (Lond), Vol: 20, Pages: s117-s118
Reynolds CJ, Watber P, Santos CNO, et al., 2020, Strong CD4 T cell responses to Zika virus antigens in a cohort of Dengue virus immune mothers of congenital Zika virus syndrome infants, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Background: There is an urgent need to understand the complex relationship between cross-reactive anti-viral immunity, disease susceptibility, and severity in the face of differential exposure to related, circulating Flaviviruses. Co-exposure to Dengue virus and Zika virus in Brazil is a case in point. A devastating aspect of the 2015-2016 South American Zika outbreak was the dramatic increase in numbers of infants born with microcephaly to mothers exposed to Zika virus during pregnancy. It has been proposed that this is more likely to ensue from Zika infection in women lacking cross-protective Dengue immunity. In this case series we measure the prevalence of Dengue immunity in a cohort of mothers exposed to Zika virus during pregnancy in the 2015-2016 Zika outbreak that gave birth to an infant affected by microcephaly and explore their adaptive immunity to Zika virus. Results: Fifty women from Sergipe, Brazil who gave birth to infants with microcephaly following Zika virus exposure during the 2015-16 outbreak were tested for serological evidence of Dengue exposure and IFNγ ELISpot spot forming cell (SFC) response to Zika virus. The majority (46/50) demonstrated Dengue immunity. IFNγ ELISpot responses to Zika virus antigens showed the following hierarchy: Env>NS1>NS3>C protein. Twenty T cell epitopes from Zika virus Env were identified. Responses to Zika virus antigens Env and NS1 were polyfunctional with cells making IFNγ, TNFα, IL-4, IL-13, and IL-10. In contrast, responses to NS5 only produced the immune regulatory TGFβ1 cytokine. There were SFC responses against Zika virus Env (1-20) and variant peptide sequences from West Nile virus, Dengue virus 1-4 and Yellow Fever virus. Conclusion: Almost all the women in our study showed serological evidence of Dengue immunity, suggesting that microcephaly can occur in DENV immune mothers. T cell immunity to Zika virus showed a multifunctional response to the antigens Env and NS1 and i
Ascough S, Ingram RJ, Chu KKY, et 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
Pinato DJ, Gramenitskaya D, Altmann DM, et al., 2019, Antibiotic therapy and outcome from immune-checkpoint inhibitors, Journal for ImmunoTherapy of Cancer, Vol: 7, ISSN: 2051-1426
Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.
Boyton RJ, Altmann DM, 2019, Muco-obstructive lung diseases, New England Journal of Medicine, Vol: 381, Pages: E20-+, ISSN: 0028-4793
Lu Y, Qiu Y, Chen P, et al., 2019, The ER-localised Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4- induced inflammation during bacterial infection, Nature Microbiology, Vol: 4, Pages: 2331-2346, ISSN: 2058-5276
The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-κB activation to produce proinflammatory cytokines for bacteria clearance, effectors with special organelle localisation have not been identified. Here, we screened over 280 E3 ubiquitin ligases and discovered that the endoplasmic reticulum-located Hrd1 regulated TLR4-induced inflammation during bacterial infection. Hrd1 directly interacted with the deubiquitinating enzyme (DUB) Usp15. Unlike the classical function of Hrd1 in ER-associated degradation, Usp15 was not degraded but lost its DUB activity for IκBα deubiquitination, resulting in excessive NF-κB activation. Importantly, Hrd1 deficiency in macrophages protected mice against LPS-induced septic shock, and knock-down of Usp15 in Hrd1 KO macrophages restored the reduced IL-6 production. This study has proposed the crosstalk between Hrd1 and TLR4 linking the ER-plasma membrane function during bacterial infection.
Chambers E, Byrne C, Morrison D, et al., 2019, Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial, Gut, Vol: 68, Pages: 1430-1438, ISSN: 0017-5749
Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses.Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.
Sim MJW, Rajagopalan S, Altmann DM, et al., 2019, Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C., Proc Natl Acad Sci U S A, Vol: 116, Pages: 12964-12973
Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01-restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.
Boyton R, Reynolds C, Chong D, et al., 2019, Bioluminescent reporting of in vivo interferon gamma immune responses during infection and autoimmunity, Journal of Immunology, Vol: 202, Pages: 2502-2510, ISSN: 1550-6606
IFN-γ is a key cytokine of innate and adaptive immunity. It is important to understand temporal changes in IFN-γ production and how these changes relate to the role of IFN-γ in diverse models of infectious and autoimmune disease, making the ability to monitor and track IFN-γ production in vivo of a substantial benefit. IFN-γ ELISPOTs have been a central methodology to measure T cell immunity for many years. In this study, we add the capacity to analyze IFN-γ responses with high sensitivity and specificity, longitudinally, in vitro and in vivo. This allows the refinement of experimental protocols because immunity can be tracked in real-time through a longitudinal approach. We have generated a novel murine IFN-γ reporter transgenic model that allows IFN-γ production to be visualized and quantified in vitro and in vivo as bioluminescence using an imaging system. At baseline, in the absence of an inflammatory stimulus, IFN-γ signal from lymphoid tissue is detectable in vivo. Reporter transgenics are used in this study to track the IFN-γ response to Pseudomonas aeruginosa infection in the lung over time in vivo. The longitudinal development of the adaptive T cell immunity following immunization with Ag is identified from day 7 in vivo. Finally, we show that we are able to use this reporter transgenic to follow the onset of autoimmune T cell activation after regulatory T cell depletion in an established model of systemic autoimmunity. This IFN-γ reporter transgenic, termed “Gammaglow,” offers a valuable new modality for tracking IFN-γ immunity, noninvasively and longitudinally over time.
Reynolds CJ, Quigley K, Cheng X, et al., 2018, Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 557-571, ISSN: 1044-1549
RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function.
Altmann DM, Reynolds CJ, Boyton RJ, 2018, Immunology of the microbiome: Implications for rheumatoid arthritis and other autoimmune diseases, The Microbiome in Rheumatic Diseases and Infection, Pages: 55-62, ISBN: 9783319790251
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Nithichanon A, Rinchai D, Buddhisa S, et al., 2018, Immune control of Burkholderia pseudomallei––common, high-frequency T-cell responses to a broad repertoire of immunoprevalent epitopes, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Burkholderia pseudomallei (Bp) is an environmental bacterial pathogen that causes potentially lethal sepsis in susceptible individuals and is considered a Category B, Tier-1 biothreat agent. As such, it is crucial to gain an improved understanding of protective immunity and potential vaccine candidates. The nature of immune correlates dictating why most exposed individuals in endemic regions undergo asymptomatic seroconversion while others succumb to life-threatening sepsis is largely uncharted. Bp seroreactive, immunogenic proteins have previously been identified by antigen microarray. We here set out to conduct an analysis of T-cell recognition of the Bp immunome using serodominant antigens represented in the original antigen microarray, examining immune correlates of disease in healthy seropositive individuals and those with acute disease or in convalescence. By screening a library of 739 overlapping peptides representing the sequences of 20 different Bp antigens, we aimed to define immune correlates of protection at the level of immunoprevalent T-cell epitopes. Responses to a large number of epitopes were common in healthy seropositive individuals: we found remarkably broad responsiveness to Bp epitopes, with 235 of 739 peptides recognized by ≥80% of all tested donors. The cumulative response to Bp epitopes in healthy, seropositive, donors from this endemic region were of the order of thousands of spot forming cells per million cells, making Bp recognition a significant component of the T-cell repertoire. Noteworthy among our findings, analysis revealed 10 highly immunoprevalent T-cell epitopes, able to induce Bp-specific IFNγ responses that were high in responding T-cell frequency within the repertoire, and also common across individuals with different human leukocyte antigen types. Acute melioidosis patients showed poor T-cell responses to the immunoprevalent epitopes, but acquired responsiveness following recovery from infection. Our findings suggest
Reynolds CJ, Suleyman OM, Ortega-Prieto AM, et al., 2018, T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses, Scientific Reports, Vol: 8, ISSN: 2045-2322
Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1–4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1–4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.
Dunachie SJ, Jenjaroen K, Reynolds CJ, et al., 2017, Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.
Lima Keesen TS, de Almeida RP, Gois BM, et al., 2017, Guillain-Barre syndrome and arboviral infection in Brazil, Lancet Infectious Diseases, Vol: 17, Pages: 693-694, ISSN: 1473-3099
Sim MJW, Malaker SA, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Immunology Meeting, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
SIM M, Malaker S, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Background.Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL 3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.Results.The impact of HLA-C bound peptide on inhibit ory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL 2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL 2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding.Conclusions.KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cros
Boelen LP, O'Neill PK, Quigley KJ, et al., 2016, BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data, PLOS Computational Biology, Vol: 12, ISSN: 1553-734X
Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.
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