ORCID Profile
0000-0002-1880-0095
Current Organisation
The University of Edinburgh
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2023
DOI: 10.1126/SCITRANSLMED.ADE3901
Abstract: Adenoviral-vectored vaccines are licensed for prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus, but, for bacterial proteins, expression in a eukaryotic cell may affect the antigen’s localization and conformation or lead to unwanted glycosylation. Here, we investigated the potential use of an adenoviral-vectored vaccine platform for capsular group B meningococcus (MenB). Vector-based candidate vaccines expressing MenB antigen factor H binding protein (fHbp) were generated, and immunogenicity was assessed in mouse models, including the functional antibody response by serum bactericidal assay (SBA) using human complement. All adenovirus-based vaccine candidates induced high antigen-specific antibody and T cell responses. A single dose induced functional serum bactericidal responses with titers superior or equal to those induced by two doses of protein-based comparators, as well as longer persistence and a similar breadth. The fHbp transgene was further optimized for human use by incorporating a mutation abrogating binding to the human complement inhibitor factor H. The resulting vaccine candidate induced high and persistent SBA responses in transgenic mice expressing human factor H. The optimized transgene was inserted into the clinically relevant ChAdOx1 backbone, and this vaccine has now progressed to clinical development. The results of this preclinical vaccine development study underline the potential of vaccines based on genetic material to induce functional antibody responses against bacterial outer membrane proteins.
Publisher: Microbiology Society
Date: 11-2013
Abstract: Streptococcus pneumoniae diseases are a rare but increasingly recognized trigger of atypical haemolytic uraemic syndrome (HUS) in young children and associated with a higher mortality rate than diarrhoea-associated HUS. This study aimed to determine the importance of neuraminidase A (NanA) and genomic ersity in the pathogenesis of pneumococcal HUS (pHUS). We investigated the nanA gene sequence, gene expression, neuraminidase activity and comparative genomic hybridization of invasive pneumococcal disease (IPD) isolates from patients with pHUS and control strains matched by serotype and sequence type (ST), isolated from patients with IPD but not pHUS. The nanA sequence of 33 isolates was determined and mutations at 142 aa positions were identified. High levels of ersity were observed within the NanA protein, with mosaic blocks, insertions and repeat regions present. When comparing nanA allelic ersity with ST and disease profile in the isolates tested, nanA alleles clustered mostly by ST. No particular nanA allele was associated with pHUS. There was no significant difference in overall neuraminidase activity between pHUS isolates and controls when induced/uninduced with N -acetylneuraminic acid. Comparative genomic hybridization showed little difference in genetic content between the pHUS isolates and the controls. Results of gene expression studies identified 12 genes differentially regulated in all pHUS isolates compared with the control. Although neuraminidase enzyme activity may be important in pHUS progression and contribute to pathogenesis, the lack of a distinction between pHUS isolates and controls suggests that host factors, such as acquired abnormalities of the alternative complement cascade in young children, may play a more significant role in the outcome of pHUS.
Publisher: Oxford University Press (OUP)
Date: 31-08-2012
DOI: 10.1093/JAC/DKS329
Publisher: Springer Science and Business Media LLC
Date: 20-01-2017
DOI: 10.1038/SREP40660
Abstract: Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus , which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin LukPQ. LukPQ is encoded on a 45 kb prophage (ΦSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.
Publisher: American Society for Microbiology
Date: 12-2015
DOI: 10.1128/AAC.01469-15
Abstract: β-Lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) is mediated by the expression of an alternative penicillin-binding protein 2a (PBP2a) (encoded by mecA ) with a low affinity for β-lactam antibiotics. Recently, a novel variant of mecA , known as mecC , was identified in MRSA isolates from both humans and animals. In this study, we demonstrate that mecC -encoded PBP2c does not mediate resistance to penicillin. Rather, broad-spectrum β-lactam resistance in MRSA strains carrying mecC ( mecC -MRSA strains) is mediated by a combination of both PBP2c and the distinct β-lactamase encoded by the blaZ gene of strain LGA251 ( blaZ LGA251 ), which is part of mecC -encoding staphylococcal cassette chromosome mec (SCC mec ) type XI. We further demonstrate that mecC -MRSA strains are susceptible to the combination of penicillin and the β-lactam inhibitor clavulanic acid in vitro and that the same combination is effective in vivo for the treatment of experimental mecC -MRSA infection in wax moth larvae. Thus, we demonstrate how the distinct biological differences between mecA - and mecC -encoded PBP2a and PBP2c have the potential to be exploited as a novel approach for the treatment of mecC -MRSA infections.
Publisher: Oxford University Press (OUP)
Date: 23-10-2013
DOI: 10.1093/JAC/DKT417
Publisher: Wiley
Date: 22-09-2015
Publisher: EMBO
Date: 25-03-2013
Publisher: American Society for Microbiology
Date: 07-2005
DOI: 10.1128/IAI.73.7.4245-4252.2005
Abstract: Complement is known to be involved in protection against systemic infection with Streptococcus pneumoniae . However, less is known about effects of complement within the lungs during pneumococcal pneumonia. By intranasally infecting transgenic mice unable to express complement C3, we investigated the role of complement in pulmonary defenses against S. pneumoniae . It was demonstrated that within the lungs, there is a requirement for C3 during the initial hours of infection. It was found that within 1 h of infection, bacterial loads decreased within lung airways of control mice as C3 protein increased. The lack of C3 resulted in the inability to control growth of wild-type or attenuated pneumococci within the lungs and bloodstream, resulting in an overwhelming inflammatory response and shorter survival times. Our results show that during the initial hours of infection with S. pneumoniae , C3 is protective within the lungs and subsequently plays an important role systemically.
Publisher: Oxford University Press (OUP)
Date: 02-12-2013
DOI: 10.1093/JAC/DKT452
Publisher: Oxford University Press (OUP)
Date: 27-11-2013
DOI: 10.1093/JAC/DKT462
Publisher: American Society for Microbiology
Date: 03-2013
DOI: 10.1128/AAC.01882-12
Abstract: Recently, a novel variant of mecA known as mecC ( mecA LGA251 ) was identified in Staphylococcus aureus isolates from both humans and animals. In this study, we identified a Staphylococcus xylosus isolate that harbors a new allotype of the mecC gene, mecC1 . Whole-genome sequencing revealed that mecC1 forms part of a class E mec complex ( mecI-mecR1-mecC1-blaZ ) located at the orfX locus as part of a likely staphylococcal cassette chromosome mec element (SCC mec ) remnant, which also contains a number of other genes present on the type XI SCC mec .
Publisher: American Society for Microbiology
Date: 2006
DOI: 10.1128/IAI.74.1.586-593.2006
Abstract: Pneumolysin, the pore-forming toxin produced by Streptococcus pneumoniae , may have an application as an immunogenic carrier protein in future pneumococcal conjugate vaccines. Most of the 90 S. pneumoniae serotypes identified produce pneumolysin therefore, this protein may confer non-serotype-specific protection against pneumococcal infections such as pneumonia, meningitis, and otitis media. However, as pneumolysin is highly toxic, a nontoxic form of pneumolysin would be a more desirable starting point in terms of vaccine production. Previous pneumolysin mutants have reduced activity but retain residual toxicity. We have found a single amino acid deletion that blocks pore formation, resulting in a form of pneumolysin that is unable to form large oligomeric ring structures. This mutant is nontoxic at concentrations greater than 1,000 times that of the native toxin. We have demonstrated that this mutant is as immunogenic as native pneumolysin without the associated effects such as production of the inflammatory mediators interleukin-6 and cytokine-induced neutrophil chemoattractant KC, damage to lung integrity, and hypothermia in mice. Vaccination with this mutant protects mice from challenge with S. pneumoniae . Incorporation of this mutant pneumolysin into current pneumococcal vaccines may increase their efficacy.
Publisher: American Society for Microbiology
Date: 11-2011
DOI: 10.1128/IAI.05592-11
Abstract: Salmonella enterica is a major cause of morbidity worldwide and mortality in children and immunocompromised in iduals in sub-Saharan Africa. Outer membrane proteins of Salmonella are of significance because they are at the interface between the pathogen and the host, they can contribute to adherence, colonization, and virulence, and they are frequently targets of antibody-mediated immunity. In this study, the properties of SadA, a purported trimeric autotransporter adhesin of Salmonella enterica serovar Typhimurium, were examined. We demonstrated that SadA is exposed on the Salmonella cell surface in vitro and in vivo during infection of mice. Expression of SadA resulted in cell aggregation, biofilm formation, and increased adhesion to human intestinal Caco-2 epithelial cells. Immunization of mice with folded, full-length, purified SadA elicited an IgG response which provided limited protection against bacterial challenge. When anti-SadA IgG titers were enhanced by administering alum-precipitated protein, a modest additional protection was afforded. Therefore, despite SadA having pleiotropic functions, it is not a dominant, protective antigen for antibody-mediated protection against Salmonella .
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
Publisher: Public Library of Science (PLoS)
Date: 15-07-2013
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Gavin Paterson.