58 results found
Astrand A, Wingren C, Benjamin A, et al., 2017, Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 174, Pages: 836-847, ISSN: 0007-1188
Gould VMW, Francis JN, Anderson KJ, et al., 2017, Nasal IgA Provides Protection against Human Influenza Challenge in Volunteers with Low Serum Influenza Antibody Titre, FRONTIERS IN MICROBIOLOGY, Vol: 8, ISSN: 1664-302X
Kinnear E, Lambert L, McDonald JU, et al., 2017, Airway T cells protect against RSV infection in the absence of antibody., Mucosal Immunol
Tissue resident memory T (Trm) cells act as sentinels and early responders to infection. Respiratory syncytial virus (RSV)-specific Trm cells have been detected in the lungs after human RSV infection, but whether they have a protective role is unknown. To dissect the protective function of Trm cells, BALB/c mice were infected with RSV; infected mice developed antigen-specific CD8(+) Trm cells (CD103(+)/CD69(+)) in the lungs and airways. Intranasally transferring cells from the airways of previously infected animals to naïve animals reduced weight loss on infection in the recipient mice. Transfer of airway CD8 cells led to reduced disease and viral load and increased interferon-γ in the airways of recipient mice, while CD4 transfer reduced tumor necrosis factor-α in the airways. Because DNA vaccines induce a systemic T-cell response, we compared vaccination with infection for the effect of memory CD8 cells generated in different compartments. Intramuscular DNA immunization induced RSV-specific CD8 T cells, but they were immunopathogenic and not protective. Notably, there was a marked difference in the induction of Trm cells; infection but not immunization induced antigen-specific Trm cells in a range of tissues. These findings demonstrate a protective role for airway CD8 against RSV and support the need for vaccines to induce antigen-specific airway cells.Mucosal Immunology advance online publication, 24 May 2017; doi:10.1038/mi.2017.46.
McDonald JU, Zhong Z, Groves HT, et al., 2017, Inflammatory responses to influenza vaccination at the extremes of age., Immunology
Age affects the immune response to vaccination, with individuals at the extremes of age responding poorly. The initial inflammatory response to antigenic materials shapes the subsequent adaptive response and so understanding is required about the effect of age on the profile of acute inflammatory mediators. In this study we measured the local and systemic inflammatory response after influenza vaccination or infection in neonatal, young adult and aged mice. Mice were immunized intramuscularly with inactivated influenza vaccine with and without the adjuvant MF59 and then challenged with H1N1 influenza. Age was the major factor affecting the inflammatory profile after vaccination: neonatal mice had more interleukin-1α (IL-1α), C-reactive protein (CRP) and granulocyte-macrophage colony-stimulating factor (GMCSF), young adults more tumour necrosis factor-α (TNF), and elderly mice more interleukin-1 receptor antagonist (IL-1RA), IL-2RA and interferon-γ-induced protein 10 (IP10). Notably the addition of MF59 induced IL-5, granulocyte colony-stimulating factor (G-CSF), Keratinocyte Chemotractant (KC) and monocyte chemoattractant protein 1 (MCP1) in all ages of animals and levels of these cytokines correlated with antibody responses. Age also had an impact on the efficacy of vaccination: neonatal and young adult mice were protected against challenge, but aged mice were not. There were striking differences in the localization of the cytokine response depending on the route of exposure: vaccination led to a high serum response whereas intranasal infection led to a low serum response but a high lung response. In conclusion, we demonstrate that age affects the inflammatory response to both influenza vaccination and infection. These age-induced differences need to be considered when developing vaccination strategies for different age groups.
Tregoning J, 2017, No researcher is too junior to fix science, NATURE, Vol: 545, Pages: 7-7, ISSN: 0028-0836
Badamchi-Zadeh A, McKay PF, Korber BT, et al., 2016, A Multi-Component Prime-Boost Vaccination Regimen with a Consensus MOMP Antigen Enghances Chlamydia trachomatis Clearance, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Gill SK, Hui K, Farne H, et al., 2016, Increased airway glucose increases airway bacterial load in hyperglycaemia, Scientific Reports, Vol: 6, ISSN: 2045-2322
Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection.We hypothesize that increased airway glucose caused by hyperglycaemia leads to increasedbacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisationis significantly more likely when blood glucose is high. We engineered mutants in genesaffecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa,strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented withglucose as the sole carbon source. The effect of glucose on growth in vivo was tested usingstreptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose.Bacterial burden in hyperglycaemic animals was greater than control animals when infected withwild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reducedboth airway glucose and bacterial load. These data support airway glucose as a criticaldeterminant of increased bacterial load during diabetes.
Hewitt R, Webber J, Farne H, et al., 2016, Airway Glucose In Virus-Induced COPD Exacerbations, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Lambert L, Kinnear E, McDonald JU, et al., 2016, DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8(+) T Cell Responses, Enabling Faster Resolution of Influenza Disease, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Mann JFS, Tregoning JS, Aldon Y, et al., 2016, CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice, JOURNAL OF CONTROLLED RELEASE, Vol: 232, Pages: 75-82, ISSN: 0168-3659
McDonald JU, Ekeruche-Makinde J, Ho MM, et al., 2016, Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex (R) xMAP (R) platform, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 433, Pages: 6-16, ISSN: 0022-1759
McDonald JU, Kaforou M, Clare S, et al., 2016, A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease., mSystems, Vol: 1
Greater understanding of the functions of host gene products in response to infection is required. While many of these genes enable pathogen clearance, some enhance pathogen growth or contribute to disease symptoms. Many studies have profiled transcriptomic and proteomic responses to infection, generating large data sets, but selecting targets for further study is challenging. Here we propose a novel data-mining approach combining multiple heterogeneous data sets to prioritize genes for further study by using respiratory syncytial virus (RSV) infection as a model pathogen with a significant health care impact. The assumption was that the more frequently a gene is detected across multiple studies, the more important its role is. A literature search was performed to find data sets of genes and proteins that change after RSV infection. The data sets were standardized, collated into a single database, and then panned to determine which genes occurred in multiple data sets, generating a candidate gene list. This candidate gene list was validated by using both a clinical cohort and in vitro screening. We identified several genes that were frequently expressed following RSV infection with no assigned function in RSV control, including IFI27, IFIT3, IFI44L, GBP1, OAS3, IFI44, and IRF7. Drilling down into the function of these genes, we demonstrate a role in disease for the gene for interferon regulatory factor 7, which was highly ranked on the list, but not for IRF1, which was not. Thus, we have developed and validated an approach for collating published data sets into a manageable list of candidates, identifying novel targets for future analysis. IMPORTANCE Making the most of "big data" is one of the core challenges of current biology. There is a large array of heterogeneous data sets of host gene responses to infection, but these data sets do not inform us about gene function and require specialized skill sets and training for their utilization. Here we describe
Porter JD, Watson J, Groves H, et al., 2016, Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium, Journal of Antimicrobial Chemotherapy, Vol: 71, Pages: 2767-2781, ISSN: 1460-2091
Background Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity.Methods In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined.Results The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5–11 μM) of rhinovirus-induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities.Conclusions The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also
Porter JD, Watson J, Roberts LR, et al., 2016, Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 71, Pages: 2767-2781, ISSN: 0305-7453
Russell RF, McDonald JU, Lambert L, et al., 2016, Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice, JOURNAL OF VIROLOGY, Vol: 90, Pages: 4735-4744, ISSN: 0022-538X
Badamchi-Zadeh A, McKay PF, Holland MJ, et al., 2015, Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies, PLOS ONE, Vol: 10, ISSN: 1932-6203
Kinnear E, Caproni LJ, Tregoning JS, 2015, A Comparison of Red Fluorescent Proteins to Model DNA Vaccine Expression by Whole Animal In Vivo Imaging, PLOS ONE, Vol: 10, ISSN: 1932-6203
Mastelic Gavillet B, Eberhardt CS, Auderset F, et al., 2015, MF59 Mediates Its B Cell Adjuvanticity by Promoting T Follicular Helper Cells and Thus Germinal Center Responses in Adult and Early Life., Journal of Immunology, Vol: 194, Pages: 4836-4845, ISSN: 0022-1767
The early life influenza disease burden calls for more effective vaccines to protect this vulnerable population. Influenza vaccines including the MF59 oil-in-water adjuvant induce higher, broader, and more persistent Ab responses in adults and particularly in young, through yet undefined mechanisms. In this study, we show that MF59 enhances adult murine IgG responses to influenza hemagglutinin (HA) by promoting a potent T follicular helper cells (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. Remarkably, this enhancement of TFH and GC B cells is already fully functional in 3-wk-old infant mice, which were fully protected by HA/MF59 but not HA/PBS immunization against intranasal challenge with the homologous H1N1 (A/California/7/2009) strain. In 1-wk-old neonatal mice, MF59 recruits and activates APCs, efficiently induces CD4(+) effector T cells and primes for enhanced infant responses but induces few fully functional TFH cells, which are mostly follicular regulatory T cells, and poor GC and anti-HA responses. The B cell adjuvanticity of MF59 appears to be mediated by the potent induction of TFH cells which directly controls GC responses both in adult and early life, calling for studies assessing its capacity to enhance the efficacy of influenza immunization in young infants.
Russell RF, McDonald JU, Ivanova M, et al., 2015, Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1 beta Responses, JOURNAL OF VIROLOGY, Vol: 89, Pages: 8974-8981, ISSN: 0022-538X
Siggins MK, Gill SK, Langford PR, et al., 2015, PHiD-CV induces anti-Protein D antibodies but does not augment pulmonary clearance of nontypeable Haemophilus influenzae in mice, VACCINE, Vol: 33, Pages: 4954-4961, ISSN: 0264-410X
Veazey RS, Siddiqui A, Klein K, et al., 2015, Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques, HUMAN VACCINES & IMMUNOTHERAPEUTICS, Vol: 11, Pages: 2913-2922, ISSN: 2164-5515
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Are Dependent on Cells of the Innate Immune System, JOURNAL OF VIROLOGY, Vol: 88, Pages: 604-611, ISSN: 0022-538X
Tregoning JS, Kinnear E, 2014, Using Plasmids as DNA Vaccines for Infectious Diseases.
DNA plasmids can be used to induce a protective (or therapeutic) immune response by delivering genes encoding vaccine antigens. That naked DNA (without the refinement of coat proteins or host evasion systems) can cross from outside the cell into the nucleus and be expressed is particularly remarkable given the sophistication of the immune system in preventing infection by pathogens. As a result of the ease, low cost, and speed of custom gene synthesis, DNA vaccines dangle a tantalizing prospect of the next wave of vaccine technology, promising individual designer vaccines for cancer or mass vaccines with a rapid response time to emerging pandemics. There is considerable enthusiasm for the use of DNA vaccination as an approach, but this enthusiasm should be tempered by the successive failures in clinical trials to induce a potent immune response. The technology is evolving with the development of improved delivery systems that increase expression levels, particularly electroporation and the incorporation of genetically encoded adjuvants. This review will introduce some key concepts in the use of DNA plasmids as vaccines, including how the DNA enters the cell and is expressed, how it induces an immune response, and a summary of clinical trials with DNA vaccines. The review also explores the advances being made in vector design, delivery, formulation, and adjuvants to try to realize the promise of this technology for new vaccines. If the immunogenicity and expression barriers can be cracked, then DNA vaccines may offer a step change in mass vaccination.
Walters AA, Kinnear E, Shattock RJ, et al., 2014, Comparative analysis of enzymatically produced novel linear DNA constructs with plasmids for use as DNA vaccines, Gene Therapy, Vol: 21, Pages: 645-652, ISSN: 1476-5462
Everitt AR, Clare S, McDonald JU, et al., 2013, Defining the Range of Pathogens Susceptible to Ifitm3 Restriction Using a Knockout Mouse Model, PLOS ONE, Vol: 8, ISSN: 1932-6203
Garnett JP, Baker EH, Naik S, et al., 2013, Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose, THORAX, Vol: 68, Pages: 835-845, ISSN: 0040-6376
Garnett JP, Baker EH, Tregoning JS, et al., 2013, Metformin Inhibits Hyperglycemia-Induced Airway Bacterial Growth And Is Associated With Reduced Transepithelial Glucose Permeability, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Mann JFS, Mckay PF, Arokiasamy S, et al., 2013, Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
Tregoning JS, Buffa V, Oszmiana A, et al., 2013, A "Prime-Pull" Vaccine Strategy Has a Modest Effect on Local and Systemic Antibody Responses to HIV gp140 in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
Tregoning JS, Wang BL, McDonald JU, et al., 2013, Neonatal antibody responses are attenuated by interferon-gamma produced by NK and T cells during RSV infection, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 5576-5581, ISSN: 0027-8424
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