Biology subjects

O'Callaghan, C. A.

Publications and source records attributed to O'Callaghan, C. A..

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↗

bioRxiv2025

Mitochondrial heterogeneity disrupts osteoclast differentiation and bone resorption by impairing respiratory complex I

Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defects. However, the mechanisms involved are generally unknown, due largely to the difficulty of manipulating mtDNA in vivo. To overcome this, we leveraged a heteroplasmic mouse model and discovered that mitochondrial heteroplasmy affects a fundamental developmental process. Specifically, the differentiation of osteoclasts, which resorb bone tissue and maintain bone homeostasis. Mechanistically, there was a reduced localization of specifically respiratory complex I subunits in mitochondria in heteroplasmic mice, disrupting ATP production and osteoclast differentiation. In addition, autophagic flux is exhausted, and the autophagy inducer spermidine restores mitochondrial health and rescues osteoclast activity, both in mice and in cells from patients with primary mitochondrial disease. Together, we identify the mechanisms by which mitochondrial heteroplasmy impacts osteoclastogenesis and discover spermidine as a modulator of this process, which presents a potential treatment for human heteroplasmic conditions such as mitochondrial diseases, which are largely untreatable. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/651799v4_ufig1.gif" ALT="Figure 1"> View larger version (94K): org.highwire.dtl.DTLVardef@131d3f6org.highwire.dtl.DTLVardef@52bf2aorg.highwire.dtl.DTLVardef@848bb3org.highwire.dtl.DTLVardef@1efa572_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

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↗