Biology subjects

Hyder-Wright, A. D.

Publications and source records attributed to Hyder-Wright, A. D..

4 recordsLinked to original sources

bioRxiv2019

Dynamic changes in innate immune and T cell function and composition at the nasal mucosa across the human lifespan

The very young and very old are at increased risk of serious infections, including pneumonia. This may relate to changes in the immune system as young children have limited immunological memory, while immunosenescence, inflammaging and a decreased pool of naive immune cells are described with advanced age. How the immune system changes with age at mucosal surfaces, from where infections frequently develop, is not very clear as access to human tissue samples is limited. Therefore, we aimed to assess the composition and activation state of the immune system at the human mucosa. Here, we profiled nasal immune cells from 207 individuals between 1 to 80 years old using flow cytometry. Neutrophil and monocyte functionality were measured using whole blood assays. Levels of thirty nasal cytokines were measured from nasal lining fluid. Nasopharyngeal colonization by Streptococcus pneumoniae was assessed using classical microbiology and associated with immune responses. We found that young children have a striking paucity of granulocytes at the nasal mucosa compared to adults. In addition, T cell numbers at the nasal mucosa decreased progressively with age and were almost absent in older adults. While nasopharyngeal colonization by Streptococcus pneumoniae was associated with elevated levels of inflammation it had a limited effect on nasal immune composition, including levels of monocytes and neutrophils. These results show that the immune system at the nasal mucosal surface changes drastically with age and provides explanations for the increased susceptibility to infections in young and old age.\n\nSignificance statementHow the immune system changes with age is an intensive area of research, but has been primarily studied in blood. However, blood poorly reflects the immune system at the mucosa, from where infections develop. This manuscript provides a first characterization of how the composition and function of the immune system in the upper respiratory tract changes with age, providing explanations for increased susceptibility to infection in the very young and old. Furthermore, by linking mucosal and systemic measurements with pneumococcal colonization, we observed that reduced monocyte and neutrophil responses associate with the increased burden of pneumococcal colonization in children. This study highlights the need to study the immune system also at other mucosal sites in the context of aging.

immunology↗

bioRxiv2019

Efficacy of PCV vaccine is primarily mediated by controlling pneumococcal colonisation density

Widespread use of Pneumococcal Conjugate Vaccines (PCV) has resulted in a reduction in nasopharyngeal colonisation and invasive pneumococcal disease caused by vaccine-types. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and a reduction in bacterial intensity (AUC) in experimentally colonised volunteers as measured by classical culture. In this study, we used a multiplex quantitative PCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the experimental colonisation status of the same trial volunteers. Increase in detection of low-density colonised volunteers by this molecular method led to a decrease of PCV efficacy against colonisation acquisition (29%), as compared to classical culture (83%). For subjects who were colonised following pneumococcal challenge, PCV had a pronounced effect on decreasing colonisation density. These results have implications for vaccine efficacy and surveillance studies as they indicate that the success of PCV vaccination could primarily be mediated by the control of vaccine-type colonisation density which results in decreased transmission and the reported herd effect of PCVs. Studies assessing the impact of PCV should account for density measurements in their design. Clinical trial registration with ISRCTN: 45340436

microbiology↗

bioRxiv2019

Defining mucosal immunity using mass cytometry following experimental human pneumococcal challenge

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonises the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples, collected following experimental human pneumococcal challenge, in order to identify immunological changes that follow and control spn colonisation. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonisation. B cell and CD8+CD161+ T cell clusters were significantly higher in non-colonised than in colonised subjects. Spn colonization led to recirculation of not only Spn-specific but also aspecific nasal B cells. This associated with increased numbers of circulating plasmablasts and increased antibody levels against the unrelated bacterium Haemophilus influenzae. In addition, we demonstrated that baseline functionality of blood mucosal associated invariant T (MAIT) cells associated with protection against Spn. These results identify new host-pathogen interactions at the mucosa upon Spn colonisation.

immunology↗

bioRxiv2018

Effect of Live Attenuated Influenza Vaccine on Pneumococcal Carriage

The widely used nasally-administered Live Attenuated Influenza Vaccine (LAIV) alters the dynamics of naturally occurring nasopharyngeal carriage of Streptococcus pneumoniae in animal models. Using a human experimental model (serotype 6B) we tested two hypotheses: 1) LAIV increased the density of S. pneumoniae in those already colonised; 2) LAIV administration promoted colonisation. Randomised, blinded administration of LAIV or nasal placebo either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes by bacterial culture and PCR. Overall acquisition for bacterial carriage were not altered by prior LAIV administration vs. controls (25/55 [45.5%] vs 24/62 [38.7%] respectively, p=0.46). Transient increase in acquisition was detected in LAIV recipients at day 2 (33/55 [60.0%] vs 25/62 [40.3%] in controls, p=0.03). Bacterial carriage densities were increased approximately 10-fold by day 9 in the LAIV recipients (2.82 vs 1.81 log10 titers, p=0.03). When immunisation followed bacterial acquisition (n=163), LAIV did not change area under the bacterial density-time curve (AUC) at day 14 by conventional microbiology (primary endpoint), but significantly reduced AUC to day 27 by PCR (p=0.03). These studies suggest that LAIV may transiently increase nasopharyngeal density of S. pneumoniae. Transmission effects should therefore be considered in the timing design of vaccine schedules.\n\nTrial registrationThe study was registered on EudraCT (2014-004634-26)\n\nFundingThe study was funded by the Bill and Melinda Gates Foundation and the UK Medical Research Council.

immunology↗