Biology subjects

Corbett, A.

Publications and source records attributed to Corbett, A..

9 recordsLinked to original sources

bioRxiv2022

Genetic Variation and Disease Severity of Respiratory Syncytial Viruses

Respiratory Syncytial Virus (RSV) disease in newborns ranges from mild symptoms to severe disease requiring hospitalization. RSV is classified into two subtypes (RSVA and RSVB) based on antigenic and genetic differences. The role these genomic variations play in disease severity remains unknown. Genome sequences were obtained using next-generation RNA sequencing on archived frozen nasal swabs of young children (< 8 months-old) infected with RSV in Rochester, NY between 1977-1998. Samples were chosen from both children hospitalized with severe RSV disease (inpatient) and those presenting with mild symptoms (outpatient) during their first cold-season. Both A and B subtypes demonstrated significant differences in the phylogeny and primary-protein structure during this time period. We found a significant association between RSV phylogeny over this time period and disease severity. For both subtypes, the G-protein demonstrated the greatest amino acid substitutions, although the number of amino acid substitutions was higher in the RSVA subtype. We found a significant association between G-protein variation and disease severity for RSVA, but not RSVB. For both subtypes, variation in the M2-2 protein was significantly associated with disease severity. These results suggest that the genetic variability of RSV proteins may contribute to disease severity in humans. ImportanceEach cold-season Respiratory Syncytial Virus (RSV) infects thousands of children in the US. Some will display mild cold symptoms while others develop severe disease, sometimes resulting in lifelong lung problems or fatality. RSV initiates infection and replicates in the nasopharynx. Substitutions in the RSV genome can be found in clinically isolated nasal-swab samples of RSV infected children. Whether these genome variations contribute to severe disease is unknown. Here we found a statistically significant association between RSV phylogeny and disease severity. Furthermore, we found specific RSV proteins (G and M2-2) whose amino acid variation was statistically associated with severe disease, although which protein was associated depended on subtype. Taken together, our results suggest that RSV genotype contributed to disease severity over this time period.

microbiology↗

bioRxiv2021

Dual TCR-alpha expression on MAIT cells as a potential confounder of TCR interpretation

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant T cell receptor (TCR) chain that uses TRAV1-2 joined to TRAJ33/20/12 and recognize metabolites from bacterial riboflavin synthesis bound to the antigen-presenting molecule, MR1. Recently, our attempts to identify alternative MR1-presented antigens led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered antigen specificity is likely to lead to altered affinity for the most potent known antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), we performed bulk TCR and {beta} chain sequencing, and single cell-based paired TCR sequencing, on T cells that bound the MR1-5-OP-RU tetramer, but with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Whereas we initially interpreted these as diverse MR1-restricted TCRs, single cell TCR sequencing revealed that cells expressing atypical TCR chains also co-expressed an invariant MAIT TCR chain. Transfection of each non-TRAV1-2 TCR chain with the TCR{beta} chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCR chain expression in human T cells and competition for the endogenous {beta} chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and non-canonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of antigen specificity.

immunology↗

bioRxiv2020

A systems genomics approach uncovers molecular associates of RSV severity

Globally, RSV infection results in millions of hospitalizations and thousands of deaths each year. Specific factors that contribute to disease severity, such as premature birth and certain comorbidities, are well established. Additionally, genetic variants resulting in alterations in the adaptive and innate immune response appear to be associated with RSV severity. While previous studies focused on a single aspect of the disease, we jointly modeled the association of disparate data modalities with RSV severity. To investigate the host response to respiratory syncytial virus (RSV) infection in infants, we performed a systems-level study of RSV pathophysiology, incorporating high-throughput measurements of the peripheral innate and adaptive immune systems and the airway epithelium and microbiota. Specifically, we developed and employed a novel multi-omic data integration method based on multilayered principal component analysis, penalized regression, and feature weight back-propagation. Our novel approach enabled us to identify cell type specific and shared cellular pathways associated with RSV severity. Of particular interest was the association between RSV severity, activation of pathways controlling Th17 and acute phase response signaling, and inhibition of B cell receptor signaling, which were present in both airway and immune cells. These data identify specific aspects of dysregulation between the humoral and mucosal response to RSV that may play a critical role in determining illness severity.

genomics↗

bioRxiv2020

Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection

RationaleRespiratory Syncytial Virus (RSV) infection is a leading cause of infant respiratory disease and hospitalization. Infant airway microbiota occupying the nasopharynx have been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease severity and infection susceptibility, are not well understood. ObjectivesTo characterize associations between the nasal microbiota and RSV infection before, during, and after infants first respiratory illness. MethodsNasal 16S rRNA microbial community profiling of two cohorts of infants in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 population matched healthy controls, and 2) an individually matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled at time points before, during, and after infection. Measurements and Main ResultsWe identified 12 taxa significantly associated with RSV infection. All 12 were differentially abundant during infection, with seven differentially abundant prior to infection, and eight differentially abundant after infection. Eight of these taxa were associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity. ConclusionsOur findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with first-time RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and the impact of RSV infection on microbiota composition. Identified taxa represent appealing targets for additional translationally-oriented research.

microbiology↗

bioRxiv2019

Insufficiency in airway interferon activation defines clinical severity to infant RSV infection

Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. Other than age at the time of infection, the causes and correlates of severe illness in infants lacking known risk factors are poorly defined. We recruited a cohort of confirmed RSV-infected infants and simultaneously assayed the presence of resident airway microbiota and the molecular status of their airways using a novel method. Rigorous statistical analyses identified a molecular airway gene expression signature of severe illness dominated by excessive chemokine expression. Global 16S rRNA sequencing confirmed an association between H. influenzae and clinical severity. Interestingly, adjusting for H. influenzae in our gene expression analysis revealed an association between severity and airway lymphocyte accumulation. Exploring the relationship between airway gene expression and the time of onset of clinical symptoms revealed a robust, acute activation of interferon (IFN) signaling, which was absent in subjects with severe illness. Finally, we explored the relationship between IFN activity, airway gene expression and productive RSV infection using a novel in vitro model of bona fide pediatric human airway epithelial cells. Interestingly, blocking IFN signaling, but not IFN ligand production, in these cells leads to increased viral infection. Our data reveal that acute airway interferon responses are physiologically relevant in the context of infant RSV infection and may be a target for therapeutic intervention. Additionally, the airway gene expression signature we define may be useful as a biomarker for efficacy of intervention responses.

genomics↗

bioRxiv2019

Airway Gene-Expression Classifiers for Respiratory Syncytial Virus (RSV) Disease Severity in Infants

BackgroundA substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness. MethodWe defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1-10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2). ResultsNGSS1 is strongly correlated with the disease severity, demonstrating a naive correlation ({rho}) of {rho}=0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%. ConclusionAirway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.

immunology↗

bioRxiv2019

Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease

The current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimers disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.

neuroscience↗

bioRxiv2019

Solid State High Throughput Screening Microscopy

We introduce a solid state high throughput screening (ssHTS) imaging modality that uses a novel Newtonian telescope design to image multiple spatially separated samples without moving parts or robotics. Conventional high-throughput imaging modalities either require movement of the sample to the focal plane of the imaging system1-3 or movement of the imaging system itself4,5, or use a wide-field approach to capture several samples in one frame. Schemes which move the sample or the imaging system can be mechanically complex and are inherently slow, while wide-field imaging systems have poor light collection efficiency and resolution compared to systems that image a single sample at a given time point. Our proposed ssHTS system uses a large parabolic reflector and an imaging lenses positioned at their focal distances above each sample. A fast LED array sequentially illuminate samples to generate images that are captured with a single camera placed at the focal point of the reflector. This optical configuration allows each sample to completely fill a sensors field of view. Since each LED illuminates a single sample and LED switch times are very fast, images from spatially separated samples can be captured at rates limited only by the cameras frame rate. The system is demonstrated by imaging cardiac monolayer and Caenorhabditis elegans (C. elegans) preparations.

bioengineering↗

bioRxiv2019

Data Resource Profile:The Dementias Platform UK (DPUK) Data Portal

The Dementias Platform UK (DPUK) Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform (UKSeRP) infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure lab using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Project are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

neuroscience↗