Biology subjects

Hill, H.

Publications and source records attributed to Hill, H..

10 recordsLinked to original sources

bioRxiv2024

Differential control of mycobacteria among COVID-19 patients is associated with CD28+ CD8+ T cells

Diseases caused by SARS-CoV-2 and Mycobacterium tuberculosis (M.tb) represent two public health emergencies. In severe disease, both pathogens may share a biological niche in the lower respiratory tract. There is significant potential for SARS-CoV-2 and M.tb infections to be co-present within individuals and enhance or moderate the respective outcomes of either infection. Here, we investigated how whole blood samples, as well as CD4+ and CD8+ T cells, from individuals hospitalised with acute COVID-19 disease respond to mycobacterial challenge. To do this, samples were assessed by ex vivo mycobacterial growth inhibition assays, immune cell phenotyping by mass cytometry, and whole blood cytokine responses to mycobacterial antigens assessed by flow cytometry. These studies identified a subgroup of COVID-19 patients whose blood had an enhanced capacity to inhibit mycobacterial growth. The ability to control mycobacterial growth was associated with the presence of a non M.tb-specific CD28+ CD8+ T cell population, with a particular activation status and migratory phenotype. This work improves our understanding of factors involved in mycobacterial control, and may contribute to the design of novel therapies for TB.

immunology↗

bioRxiv2022

A cell-based, spike protein binding assay highlights differences in antibody neutralising capacity for SARS-CoV-2 variants

The engagement of the SARS-CoV-2 spike protein with ACE2 is a critical step for viral entry to human cells and accordingly blocking this interaction is a major determinant of the efficacy of monoclonal antibody therapeutics and vaccine-elicited serum antibodies. The emergence of SARS-CoV-2 variants necessitates the development of adaptable assays that can be applied to assess the effectiveness of therapeutics. Through testing of a range of recombinant spike proteins, we have developed a cell based, ACE2/spike protein binding assay that characterises monoclonal anti-spike protein antibodies and neutralising antibodies in donor serum. The assay uses high-content imaging to quantify cell bound spike protein fluorescence. Using spike proteins from the original Wuhan SARS-CoV-2 virus, as well as the delta and omicron variants, we identify differential blocking activity of three monoclonal antibodies directed against the spike receptor binding domain. Importantly, biological activity in the spike binding assay translated to efficacy in a SARS-CoV-2 infection assay. Hence, the spike binding assay has utility to monitor anti-spike antibodies against the major known SARS-CoV-2 variants and is readily adaptable to quantify impact of antibodies against new and emerging SARS-CoV-2 variants.

cell biology↗

bioRxiv2019

Studying global processing in autism and attention-deficit/hyperactivity disorder with gaze movements: The example of a copying task

Recent discussions in the literature, along with the revision of the Diagnostic and Statistical Manual (DSM) [2], suggest aetiological commonalities between the highly comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Addressing this discussion requires studying these disorders together by comparing constructs typical to each of them. In the present study, we investigate global processing, known to be difficult for participants with ASD, and Intra-Subject Variability (ISV), known to be consistently increased in participants with ADHD, in groups, aged 10-13 years, with ADHD (n=25), ASD without comorbid ADHD (ASD-) (n=13) and ASD with ADHD (ASD+) (n=18) in comparison with a typically developing group (n=22). A Copying task, typically requiring global processing and in this case particularly designed using equally complex stimuli to also measure ISV across trials, was selected. Oculomotor measures in this task proved to be particularly sensitive to group differences. While increased ISV was not observed in the present task in participants with ADHD, both ASD groups needed to look longer on the figure to be drawn, indicating that global processing takes longer in ASD. However, the ASD+ group needed to fixate on the figure only between drawing movements, whereas the ASD-group needed to do this throughout the drawing process. The present study provides evidence towards ASD and ADHD being separate, not-overlapping, disorders. Since the pure ASD-group was affected more by central coherence problems than the ASD+ group, it may suggest that neuropsychological constructs interact differently in different clinical groups and sub-groups.

neuroscience↗

bioRxiv2019

Exploring the limitations of event-related potential measures in moving subjects. Case studies of four different technical modifications in ergometer rowing

Measuring brain activity outside the laboratory is of great importance for investigating human behavior under naturalistic conditions (e.g., in cognition and movement research, application of brain-computer interfaces). To measure neuronal activity in moving subjects, only modified NIRS and EEG systems are applicable. Because conventional EEG systems are too sensitive to movement artifacts, artifact sources should be eliminated beforehand to improve signal quality. Four different approaches for EEG/ERP measures with moving subjects were tested in case studies: (i) a purpose-built head-mounted preamplifier, (ii) a laboratory system with active electrodes, (iii)+(iv) a wireless headset combined with (iii) passive or (iv) active electrodes. A standard visual oddball task was applied during rest (without movement) and during ergometer rowing. All 14 measures revealed very similiar (within subjects) visual evoked potentials for rowing and rest. The small intraindividual differences between rowing and rest, in comparison to the typically larger interindividual differences in the ERP waveforms revealed that ERPs can be measured reliably even in an athletic movement like rowing. The expected modulation of the motor-related activity by force output, on the other hand, was largely affected by movement artifacts. Therefore, for a successful application of ERP measures in movement research, further developments to differentiate between movement-related neuronal activity and movement-related artifacts are required. However, it cannot be excluded that activities with small magnitudes related to motor learning and motor control cannot be detected because they are superimposed by the very large motor potential which increases with force output.

neuroscience↗

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

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

Experimental Human Challenge Reveals Distinct Mechanisms of Acquisition or Protection Against Pneumococcal Colonization

Colonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae. Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after pneumococcal exposure. We found that nasal colonization can take up to 24 hours to become established. Also, two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at one-hour post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 hours post bacterial encounter.

immunology↗

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↗

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↗