Biology subjects

Quinlan, R.

Publications and source records attributed to Quinlan, R..

3 recordsLinked to original sources

bioRxiv2025

Accelerated memory T cell decline and tolerogenic recall responses to SARS-CoV-2 vaccination in diabetes

Type 1 and type 2 diabetes are associated with increased severity and mortality from respiratory virus infections, including SARS-CoV-2. Vaccination in the general population significantly reduces the risk of severe respiratory viral infection and triggers a strong, polyfunctional and lasting T cell response in healthy individuals. However, vaccine effectiveness in people with diabetes is unclear. Here we studied the magnitude and functional characteristics of vaccine-specific CD4+ and CD8+ T cell responses to the full vaccination protocol, and the recall response after a third booster dose of SARS-CoV-2 vaccine in people with type 1 and type 2 diabetes, and compared them to those of people without diabetes. We found defects in both CD4+ and CD8+ T cell memory maintenance and the functionality of the vaccine specific T cells in people with diabetes compared to people without. In those individuals with diabetes that harbored detectable vaccine-specific T cells, they displayed an unfocused, tolerogenic phenotype characterized by increased expression of IL-13 and IL-10 in T1D and T2D compared to people without diabetes. These results have implications for vaccination strategies for people with diabetes.

immunology↗

bioRxiv2022

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature upon SARS-CoV-2 sensing by monocytes in COVID-19

Alterations in the myeloid immune compartment have been observed in COVID-19, but the specific mechanisms underlying these impairments are not completely understood. Here we examined the functionality of classical CD14+ monocytes as a main myeloid cell component in well-defined cohorts of patients with mild and moderate COVID-19 during the acute phase of infection and compared them to that of healthy individuals. We found that ex vivo isolated CD14+ monocytes from mild and moderate COVID-19 patients display specific patterns of costimulatory and inhibitory receptors that clearly distinguish them from healthy monocytes, as well as altered expression of histone marks and a dysfunctional metabolic profile. Decreased NF{kappa}B activation in COVID-19 monocytes ex vivo is accompanied by an intact type I IFN antiviral response. Subsequent pathogen sensing ex vivo led to a state of functional unresponsiveness characterized by a defect in pro-inflammatory cytokine expression, NF{kappa}B-driven cytokine responses and defective type I IFN response in moderate COVID-19 monocytes. Transcriptionally, COVID-19 monocytes switched their gene expression signature from canonical innate immune functions to a pro-thrombotic phenotype characterized by increased expression of pathways involved in hemostasis and immunothrombosis. In response to SARS-CoV-2 or other viral or bacterial components, monocytes displayed defects in the epigenetic remodelling and metabolic reprogramming that usually occurs upon pathogen sensing in innate immune cells. These results provide a potential mechanism by which innate immune dysfunction in COVID-19 may contribute to disease pathology.

immunology↗

bioRxiv2020

Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreichs ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by approximately 1.5-fold in the reporter cell line and in several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogues were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

neuroscience↗