Biology subjects

German, E. L.

Publications and source records attributed to German, E. L..

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

Minimally-invasive nasal sampling in children offers accurate pneumococcal colonization detection

Nasopharyngeal colonization of potential respiratory pathogens such as Streptococcus pneumoniae is the major source of transmission and precursor of invasive disease. Swabbing deeply the nasopharynx, which is currently recommended by WHO, provides accurate pneumococcal detection but is unpleasant. We showed that nasal lining fluid filter strips offer equal detection sensitivity.

microbiology↗

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↗

bioRxiv2018

Inflammation induced by influenza virus impairs innate control of human pneumococcal carriage

Secondary bacterial pneumonia following influenza infection is a significant cause of mortality worldwide. Upper respiratory tract pneumococcal carriage is important as both determinants of disease and population transmission. The immunological mechanisms that contain pneumococcal carriage are well-studied in mice but remain unclear in humans. Loss of this control of carriage following influenza infection is associated with secondary bacterial pneumonia during seasonal and pandemic outbreaks. We used a human type 6B pneumococcal challenge model to show that carriage acquisition induces early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function associated with clearance of pneumococcal carriage. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate function and altered genome-wide nasal gene responses to pneumococcal carriage. Levels of the cytokine IP-10 promoted by viral infection at the time of pneumococcal encounter was positively associated with bacterial density. These findings provide novel insights in nasal immunity to pneumococcus and viral-bacterial interactions during co-infection.

immunology↗