ORCID Profile
0000-0003-4797-4710
Current Organisation
Murdoch Children's Research Institute
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Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
DOI: 10.1038/S41467-019-10814-9
Abstract: Streptococcus pneumoniae is the main bacterial pathogen involved in pneumonia. Pneumococcal acquisition and colonization density is probably affected by viral co-infections, the local microbiome composition and mucosal immunity. Here, we report the interactions between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity using an experimental human challenge model. Nasal microbiota profiles at baseline are associated with consecutive pneumococcal carriage outcome (non-carrier, low-dense and high-dense pneumococcal carriage), independent of LAIV co-administration. Corynebacterium / Dolosigranulum -dominated profiles are associated with low-density colonization. Lowest rates of natural viral co-infection at baseline and post-LAIV influenza replication are detected in the low-density carriers. Also, we detected the fewest microbiota perturbations and mucosal cytokine responses in the low-density carriers compared to non-carriers or high-density carriers. These results indicate that the complete respiratory ecosystem affects pneumococcal behaviour following challenge, with low-density carriage representing the most stable ecological state.
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Thoracic Society
Date: 05-2019
Publisher: European Respiratory Society (ERS)
Date: 31-03-2022
DOI: 10.1183/23120541.00586-2021
Abstract: Streptococcus pneumoniae (pneumococcus) is the most commonly identified bacterial cause of pneumonia and the leading infectious cause of death in children under 5 years of age worldwide. Pneumococcal disease follows a seasonal pattern with increased incidence during winter. Pneumonia burden is also associated with poor air quality. Nasopharyngeal carriage of the bacterium is a pre-requisite of invasive disease. We aimed to determine if susceptibility to nasopharyngeal pneumococcal carriage varied by season and which environmental factors might explain such variation. We also evaluated the influence of sex on susceptibility of carriage. We collated data from five studies in which human volunteers underwent intranasal pneumococcal challenge. Generalised linear mixed-effects models were used to identify factors associated with altered risk of carriage acquisition, specifically climate and air-quality data. During 2011–2017, 374 healthy adults were challenged with type 6B pneumococcus. Odds of carriage were significantly lower in males (OR, 0.61 95% CI, 0.40–0.92 p=0.02), and higher with cooler temperatures (OR, 0.79 95% CI, 0.63–0.99 p=0.04). Likelihood of carriage was also associated with lower concentrations of local fine particulate matter concentrations (PM 2.5 ) and increased local rainfall. In contrast to epidemiological series, experimental challenge allowed us to test propensity to acquisition during controlled exposures immunological explanations for sex and climatic differences should be sought.
Publisher: American Thoracic Society
Date: 15-12-2016
Publisher: American Society for Clinical Investigation
Date: 16-09-2019
DOI: 10.1172/JCI128865
Publisher: American Thoracic Society
Date: 03-2021
Publisher: American Thoracic Society
Date: 12-2022
Publisher: Elsevier BV
Date: 02-2022
Publisher: Wiley
Date: 14-09-2017
DOI: 10.1111/COA.12956
Abstract: Saline irrigation of the nasal cavity and paranasal sinuses has a recognised role in the management of chronic rhinosinusitis. However, bacterial recontamination of irrigation bottles through backflow from the sinonasal cavity is a concern in recurrent sinus cavity infections. While patients are encouraged to clean the irrigation bottles regularly, there remains significant concern that the use of contaminated bottles may perpetuate chronic rhinosinusitis. This study assesses the optimal microwave duration to achieve decontamination for each irrigation bottle component part (reservoir, tube and nozzle) using a standard, commercially available microwave. In addition, the irrigation fluid was also tested for contamination after each microwave cycle. Laboratory-based experimental study. No patients were involved in this study. The percentage in vitro decontamination of the bottles' components was determined following 30, 60, 90, 120, 150 seconds of microwave cycles. Complete decontamination of the bottles was not achieved at any of the tested microwave cycles. Levels of decontamination differed for the different bottle components, and the greatest degree of decontamination for all bottle components occurred at 90 seconds. Although higher levels of decontamination were observed at microwave durations exceeding 90 seconds, this was at the expense of thermal degradation and deformation of the reservoir plastic component of the irrigation bottle. Similarly, lowest contamination of irrigation fluid was observed at 120 seconds. This study highlights the importance of establishing precise decontamination procedures and recommends a microwave cycle of 90 seconds for optimal decontamination.
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2020
DOI: 10.1101/2020.04.23.20077073
Abstract: Pneumococcal colonisation is key to the pathogenesis of invasive disease, but is also immunogenic in young adults, protecting against re-colonisation. Colonisation is rarely detected in older adults, despite high rates of pneumococcal disease. To establish experimental human pneumococcal colonisation in healthy adults aged 50—84 years, to measure the immune response to pneumococcal challenge, and to assess the protective effect of prior colonisation against autologous strain rechallenge. Sixty-four participants were inoculated with Streptococcus pneumoniae (serotype 6B, 80,000CFU in each nostril). Colonisation was determined by bacterial culture of nasal wash, serum anti-6B capsular IgG responses by ELISA, and anti-protein immune responses by multiplex electrochemiluminescence. Experimental colonisation was established in 39% of participants (25/64) with no adverse events. Colonisation occurred in 47% (9/19) of participants aged 50—59 compared with 21% (3/14) in those aged ≥70 years. Previous pneumococcal polysaccharide vaccination did not protect against colonisation. Colonisation did not confer serotype-specific immune boosting: GMT (95% CI) 2.7μg/mL (1.9—3.8) pre-challenge versus 3.0 (1.9—4.7) four weeks post-colonisation (p = 0.53). Furthermore, pneumococcal challenge without colonisation led to a drop in specific antibody levels from 2.8μg/mL (2.0—3.9) to 2.2μg/mL (1.6—3.0) post-challenge (p = 0.006). Anti-protein antibody levels increased following successful colonisation. Rechallenge with the same strain after a median of 8.5 months (IQR 6.7—10.1) led to recolonisation in 5/16 (31%). In older adults, experimental pneumococcal colonisation is feasible and safe, but demonstrates different immunological outcomes compared with younger adults in previous studies.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2018
Publisher: MDPI AG
Date: 06-06-2020
Abstract: Pneumonia is the sixth largest cause of death in the UK. It is usually caused by Streptococcus pneumoniae, which healthy in iduals can carry in their nose without symptoms of disease. Antimicrobial resistance further increases mortality and morbidity associated with pneumococcal infection, although few studies have analysed resistance in naturally circulating pneumococcal isolates in adult populations. Here, we report on the resistome and associated mobile genetic elements within circulating pneumococcus isolated from adult volunteers enrolled in the experimental human pneumococcal colonisation (EHPC) research program at the Liverpool School of Tropical Medicine, UK. Pneumococcal isolates collected from 30 healthy asymptomatic adults who had volunteered to take part in clinical research were screened for antibiotic susceptibility to erythromycin and tetracycline, and whole-genome sequenced. The genetic context of resistance to one or both antibiotics in four isolates was characterised bioinformatically, and any association of the resistance genes with mobile genetic elements was determined. Tetracycline and macrolide resistance genes [tet(M), erm(B), mef(A), msr(D)] were detected on known Tn916-like integrative and conjugative elements, namely Tn6002 and Tn2010, and tet(32) was found for the first time in S. pneumoniae located on a novel 50 kb genomic island. The widespread use of pneumococcal conjugate vaccines impacts on serotype prevalence and transmission within the community. It is therefore important to continue to monitor antimicrobial resistance (AMR) genes present in both vaccine types and non-vaccine types in response to contemporary antimicrobial therapies and characterise the genetic context of acquired resistance genes to continually optimise antibiotic therapies.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Oxford University Press (OUP)
Date: 28-01-2019
Publisher: American Society for Clinical Investigation
Date: 04-2022
DOI: 10.1172/JCI157124
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2019
Publisher: American Society for Microbiology
Date: 23-02-2021
Abstract: Occurrence of lower respiratory tract infections requires prior colonization of the upper respiratory tract with a pathogen. Most bacterial infection and colonization studies have been performed in murine and in vitro models due to the current invasive s ling methodology of the upper respiratory tract, both of which poorly reflect the complexity of host-pathogen interactions in the human nose.
Publisher: Cold Spring Harbor Laboratory
Date: 21-02-2022
DOI: 10.1101/2022.02.20.480002
Abstract: Characterising the genetic ersity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition, and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic ersity of Streptococcus pneumoniae within in idual infants and their mothers by deep sequencing whole pneumococcal populations from longitudinal nasopharyngeal s les. We demonstrate deep sequencing has unsurpassed sensitivity for detecting multiple colonisation, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared to gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child’s life. Comprehensive treatment data demonstrated infants were at an elevated risk of both the acquisition, and persistent colonisation, of a multidrug resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonisation imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens.
Publisher: American Society for Clinical Investigation
Date: 26-01-2021
Publisher: European Respiratory Society (ERS)
Date: 10-2018
Publisher: Public Library of Science (PLoS)
Date: 12-02-2021
DOI: 10.1371/JOURNAL.PONE.0247056
Abstract: Older adults are at increased risk of pneumococcal disease. This work aims to evaluate whether there is any decrease in serum IgG against variants of the antigens Pneumococcal surface protein A (PspA) and Pneumococcal surface protein C (PspC) in healthy adults with increasing age. Levels of IgG against PspA and PspC variants were determined by ELISA in serum s les comparing volunteers 18–30 years of age with volunteers who were 50–70+ before and after an experimental pneumococcal colonization challenge. The serotype 6B strain used in the challenge belongs to a minor group of pneumococcal isolates expressing two PspC variants. There was a decrease in levels of IgG with increasing age for the most common PspA variants and for all PspC variants analyzed. No correlation was found between basal levels of IgG against these antigens and protection against colonization. There was an increase in levels of IgG against PspA variants that are more cross-reactive with the variant expressed by the challenge strain post challenge in younger in iduals who became colonized. Since the challenge strain used in our study expresses two different PspC variants, an increase in serum IgG against all PspC variants tested was observed in younger in iduals who became colonized. For some of the antigen variants tested, a decrease in serum IgG was observed in young volunteers who were challenged but did not become colonized. Serum IgG antibodies against PspA and PspC variants thus decrease with age in healthy adults, but there is no correlation between levels of IgG against these antigens and protection against human experimental colonization. Though no correlation between naturally induced serum IgG antibodies against PspA and PspC and protection against colonization was observed, these results do not rule out the protective potential of these antigens as vaccines against pneumococcal infections.
Publisher: American Thoracic Society
Date: 02-2020
Publisher: American Society for Clinical Investigation
Date: 06-2022
DOI: 10.1172/JCI161565
Publisher: Springer Science and Business Media LLC
Date: 14-09-2021
DOI: 10.1038/S41598-021-97807-1
Abstract: Previous studies have suggested that the pneumococcal niche changes from the nasopharynx to the oral cavity with age. We use an Experimental Human Pneumococcal Challenge model to investigate pneumococcal colonisation in different anatomical niches with age. Healthy adults (n = 112) were intranasally inoculated with Streptococcus pneumoniae serotype 6B (Spn6B) and were categorised as young 18–55 years (n = 57) or older 55 years (n = 55). Colonisation status (frequency and density) was determined by multiplex qPCR targeting the lytA and cpsA -6A/B genes in both raw and culture-enriched nasal wash and oropharyngeal swab s les collected at 2-, 7- and 14-days post-exposure. For older adults, raw and culture-enriched saliva s les were also assessed. 64% of NW s les and 54% of OPS s les were positive for Spn6B in young adults, compared to 35% of NW s les, 24% of OPS s les and 6% of saliva s les in older adults. Many colonisation events were only detected in culture-enriched s les. Experimental colonisation was detected in 72% of young adults by NW and 63% by OPS. In older adults, this was 51% by NW, 36% by OPS and 9% by saliva. The nose, as assessed by nasal wash, is the best niche for detection of experimental pneumococcal colonisation in both young and older adults.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2019
DOI: 10.1038/S41467-019-11005-2
Abstract: Control of Streptococcus pneumoniae colonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Here, we use an experimental human pneumococcal carriage model (EHPC) to show that S. pneumoniae colonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium shaped the host transcriptomic response in vitro. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling and regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. Our results indicate that, rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances inflammatory and innate immune responses associated with clearance.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Elissavet Nikolaou.