Biology subjects

Davison, L. J.

Publications and source records attributed to Davison, L. J..

3 recordsLinked to original sources

bioRxiv2025

Fatal consequences of feline coronavirus infection are associated with virus persistence and a distinct adaptive immune repertoire

The pathogenesis of feline infectious peritonitis (FIP), arising in a minority of cats infected with feline coronavirus (FCoV), is complex and incompletely understood. Without extended use of direct-acting antivirals FIP is invariably fatal, but there is potential for the emergence of anti-viral resistance. To understand host and viral factors associated with FIP, multiple tissues from cats with and without FIP were subjected to RNA sequencing (RNA-seq), and targeted sequencing of the T cell receptor (TCR) repertoire was conducted for mesenteric lymph nodes in a larger cohort. Samples from cats with FIP demonstrated higher expression of genes involved in type I interferon and proinflammatory cytokine signalling, as well as the adaptive immune response, and expression of these genes was highly correlated with FCoV abundance. Analysis of FCoV genomic variation across tissues revealed dynamic within-host evolution of FCoV, and identified distinct mutations associated with systemic virus spread both within and among cats. Assembly of TCR and B-cell receptor (BCR) sequences identified changes in the immune repertoire associated with FIP, highlighting the polyclonality and ineffectiveness of the immune response to FCoV in cats with FIP, and revealing the presence of potentially protective TCR clonotypes in cats without FIP. Together, these results represent the first analysis of immune repertoire in any feline infectious disease and demonstrate naturally occurring within-host evolution of FCoV. These novel insights into a life-threatening systemic coronaviral disease have the potential to transform therapeutic approaches in FIP.

immunology↗

bioRxiv2023

Partitioning heritability using single-cell multi-omics identifies a novel macrophage subpopulation conveying genetic risks of coronary artery disease.

BackgroundCoronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. While over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages. MethodsWe utilized single-cell RNA-seq (scRNA-seq) and single-cell multi-omics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis--the formation of lipid-laden foam cells. Meta-analysis of scRNA-seq datasets from 26 human plaque samples was undertaken to provide a comprehensive atlas of lesional macrophages and to correlate subpopulations in vivo and ex vivo. The genetic risk levels of CAD were assessed by partitioning disease heritability across different macrophage subpopulations. ResultsWe identified a novel macrophage subpopulation, termed lipid-handling macrophages, both ex vivo and in vivo, and identified associated marker genes, transcription regulators, and functional pathways. 18,782 cis-regulatory elements were identified by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD GWAS data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of lipid-handling macrophages. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-beta in the causal mechanisms at this locus. ConclusionsOur results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key sub-population through which genetic variants actively influence disease. These findings provide an unbiased framework for functional fine-mapping of GWAS results using single-cell multi-omics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

genetics↗

bioRxiv2018

Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

Non-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identified DEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lower DEXI expression. Here, we demonstrate by CRISPR mutagenesis in vivo and deep phenotyping that disrupted Dexi expression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by which DEXI alters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.\n\nOne Sentence Summary: Disruption of the Dexi gene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.

genetics↗