Biology subjects

Comerford, I.

Publications and source records attributed to Comerford, I..

3 recordsLinked to original sources

bioRxiv2025

RUNX2 is a cell-intrinsic brake on Th17 pathogenicity driven by neutrophil extracellular traps

Th17 cells are crucial mediators of protective immunity against extracellular pathogens but also promote inflammatory responses in pathological settings such as MS. Distinct transcriptional programs can generate Th17 populations termed pathogenic or non-pathogenic. Understanding the transcriptional regulation of these T cell states is emerging and presents opportunities to modulate pathogenic T cell responses. In this study, we demonstrate that pro-inflammatory Th17 cells in MS and EAE express high levels of the transcription factor RUNX2. T cell specific deletion of RUNX2 lowers the threshold for induction of CNS autoimmunity in mice by increasing generation of pathogenic GM-CSF-expressing Th17 cells. RUNX2-dependent inhibition of pathogenic Th17 priming relied on the extent of neutrophil-driven pathogenic Th17 priming in vivo. EAE-induced immature neutrophils elicit more pathogenic Th17 cells in the absence of RUNX2 in T cells, an effect reliant on neutrophil-derived extracellular traps. These data uncover a role for RUNX2 in suppressing NET-driven Th17 pathogenicity and suggest that increasing RUNX2 activity in T cells may be a strategy to constrain pathological inflammatory responses where Th17 cells and inflammatory neutrophils interplay.

immunology↗

bioRxiv2022

Novel populations of Tr1 cells contribute to the resolution of acute influenza A virus infection.

Type I regulatory (Tr1) cells contribute to immune suppression in the context of chronic infection, autoimmunity, and transplant tolerance. However, their physiological relevance in the resolution of acute respiratory infection is not understood. Here, we identify Tr1 cells accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus infection in mice. Tr1 cells were dependent on IL-27R and in their absence recovery from IAV-induced weight loss is impaired. Notably, these Tr1 cells did not necessarily co-express the typical Tr1 markers LAG-3 and CD49b, with four distinct populations of Tr1 cells apparent in the lungs. Each population was suppressive and were differentially dependent on IL-10 to mediate suppression. Transcriptional analysis revealed a core Tr1 gene signature in each population and distinct expression profiles indicative of different states of activation and differentiation. Finally, sort-transfer experiments indicated non-linear plasticity between these subsets of Tr1 cells. Together, these data support Tr1 cells contributing to the resolution of acute inflammation and define novel Tr1 cell phenotypes in acute infection.

immunology↗

bioRxiv2019

In Vivo Dual RNA-Seq Analysis Reveals the Basis for Differential Tissue Tropism of Clinical Isolates of Streptococcus pneumoniae

Streptococcus pneumoniae is a genetically diverse human-adapted pathogen commonly carried asymptomatically in the nasopharynx. We have recently shown that a single nucleotide polymorphism (SNP) in the raffinose pathway regulatory gene rafR accounts for a significant difference in the capacity of clonally-related strains to cause localised versus systemic infection. Here we have used dual RNA-seq to show that this SNP extensively impacts both bacterial and host transcriptomes in infected lungs. It affects expression of bacterial genes encoding multiple sugar transporters, and fine-tunes carbohydrate metabolism, along with extensive rewiring of host transcriptional responses to infection, particularly expression of genes encoding cytokine and chemokine ligands and receptors. The dual RNA-seq data predicted a crucial role for differential neutrophil recruitment in the distinct virulence profiles of the infecting strains and single cell analysis revealed that while reduced expression of the RafR regulon driven by a single rafR SNP provides a clear advantage for pneumococci to colonize the ear, in the lung it leads to massive recruitment of neutrophils and bacterial clearance. Importantly, the observed disease outcomes were confirmed by in vivo neutrophil depletion showing that early detection of bacteria by the host in the lung environment is crucial for effective clearance. Thus, dual RNA-seq provides a powerful tool for understanding complex host-pathogen interactions and revealed how a single bacterial SNP can drive differential disease outcomes.

microbiology↗