Biology subjects

Dwyer, D.

Publications and source records attributed to Dwyer, D..

4 recordsLinked to original sources

bioRxiv2022

Type 2 Inflammation Drives an Airway Basal Stem Cell Program Through Insulin Receptor Substrate Signaling

BackgroundChronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal epithelial cells (BCs). Recent studies have identified transcriptionally distinct BCs, but functional data are lacking and the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown. ObjectiveTo determine the role of T2 cytokines in regulating airway BCs MethodsSingle cell and bulk RNA-sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of IL4R inhibitors. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and repair. ResultsHere we find two subsets of BCs in human and murine respiratory mucosa distinguished by the expression of BC adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/13 increases expression of BCAM and TP63 through an Insulin Receptor Substrate (IRS)-dependent signaling pathway that is increased in CRSwNP. ConclusionsThese findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation. CAPSULE SUMMARYType 2 cytokines drive an airway stem cell program through IRS signaling KEY MESSAGESO_LITwo subsets of airway BCs have distinct transcriptional signatures and function C_LIO_LIHigh levels of BCAM expression mark the earliest BC progenitor C_LIO_LIIL-4 and IL-13 upregulate BCAM and P63 in an IRS-dependent fashion which prevents BC differentiation to secretory epithelial cells C_LIO_LIBCAMhi BCs are increased in CRSwNP C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/512129v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@16e78e8org.highwire.dtl.DTLVardef@1c40393org.highwire.dtl.DTLVardef@1c6bc4aorg.highwire.dtl.DTLVardef@73b9db_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Longitudinal characterisation of phagocytic and neutralisation functions of anti-Spike antibodies in plasma of patients after SARS-CoV-2 infection.

Phagocytic responses by effector cells to antibody or complement-opsonised viruses have been recognized to play a key role in anti-viral immunity. These include antibody dependent cellular phagocytosis mediated via Fc-receptors, phagocytosis mediated by classically activated complement-fixing IgM or IgG1 antibodies and antibody independent phagocytosis mediated via direct opsonisation of viruses by complement products activated via the mannose-binding lectin pathway. Limited data suggest these phagocytic responses by effector cells may contribute to the immunological and inflammatory responses in SARS-CoV-2 infection, however, their development and clinical significance remain to be fully elucidated. In this cohort of 62 patients, acutely ill individuals were shown to mount phagocytic responses to autologous plasma-opsonised SARS-CoV-2 Spike protein-coated microbeads as early as 10 days post symptom onset. Heat inactivation of the plasma prior to use as an opsonin caused 77-95% abrogation of the phagocytic response, and pre-blocking of Fc-receptors on the effector cells showed only 18-60% inhibition. These results suggest that SARS-CoV-2 can provoke early phagocytosis, which is primarily driven by heat labile components, likely activated complements, with variable contribution from anti-Spike antibodies. During convalescence, phagocytic responses correlated significantly with anti-Spike IgG titers. Older patients and patients with severe disease had significantly higher phagocytosis and neutralisation functions when compared to younger patients or patients with asymptomatic, mild, or moderate disease. A longitudinal study of a subset of these patients over 12 months showed preservation of phagocytic and neutralisation functions in all patients, despite a drop in the endpoint antibody titers by more than 90%. Interestingly, surface plasmon resonance showed a significant increase in the affinity of the anti-Spike antibodies over time correlating with the maintenance of both the phagocytic and neutralisation functions suggesting that improvement in the antibody quality over the 12 months contributed to the retention of effector functions. Author SummaryLimited data suggest antibody dependent effector functions including phagocytosis may contribute to the immunological and inflammatory responses in SARS CoV-2 infection, however, their development, maintenance, and clinical significance remain unknown. In this study we show: O_LIPatients with acute SARS CoV-2 infection can mount phagocytic responses as early as 10 days post symptom onset and these responses were primarily driven by heat labile components of the autologous plasma. These results indicate that the current approach of studying phagocytosis using purified or monoclonal antibodies does not recapitulate contribution by all components in the plasma. C_LIO_LIIn convalescent patients, high phagocytic responses significantly correlated with increasing age, increasing disease severity, high neutralisation functions and high anti-Spike antibody titers, particularly IgG1. C_LIO_LILongitudinal study of convalescent patients over a 12-month period showed maintenance of phagocytic and neutralisation functions, despite a drop in the anti-Spike endpoint antibody titers by more than 90%. However, we found significant increase in the affinity of the anti-Spike antibodies over the 12-month period and these correlated with the maintenance of functions suggesting that improvement in the antibody quality over time contributed to the retention of effector functions. Clinically, measuring antibody titers in sera but not the quality of antibodies is considered a gold standard indicator of immune protection following SARS-CoV 2 infection or vaccination. Our results challenge this notion and recommends change in the current clinical practice. C_LI

immunology↗

bioRxiv2021

dsMTL - a computational framework for privacy-preserving, distributed multi-task machine learning

Multitask learning allows the simultaneous learning of multiple communicating algorithms. It is increasingly adopted for biomedical applications, such as the modeling of disease progression. As data protection regulations limit data sharing for such analyses, an implementation of multitask learning on geographically distributed data sources would be highly desirable. Here, we describe the development of dsMTL, a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. dsMTL is implemented as a library for the R programming language and builds on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. We provide a comparative evaluation of dsMTL for the identification of biological signatures in distributed datasets using two case studies, and evaluate the computational performance of the supervised and unsupervised algorithms. dsMTL provides an easy- to-use framework for privacy-preserving, federated analysis of geographically distributed datasets, and has several application areas, including comorbidity modeling and translational research focused on the simultaneous prediction of different outcomes across datasets. dsMTL is available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package).

bioinformatics↗

bioRxiv2020

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.

physiology↗