Biology subjects

Oldham, J. M.

Publications and source records attributed to Oldham, J. M..

3 recordsLinked to original sources

bioRxiv2026

Novel Streptococcus mitis subsp. mitis Picklauza buccal isolate from individual with idiopathic pulmonary fibrosis containing functional mobile qacG Gene.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by immune dysregulation, fibrosis, and eventual respiratory failure. While the etiology of IPF remains unclear, accumulating evidence implicates the oral and airway microbiome in disease progression, with elevated Streptococcal burden linked to increased mortality. Whether specific taxa actively contribute to IPF pathophysiology or arise secondarily from the damaged lung environment remains unresolved. Here, we characterize "Picklauza," a streptococcal strain isolated from the buccal mucosa of an individual with IPF. Although its average nucleotide identity to a Streptococcus mitis reference genome was 93.855%, analysis with Streptoquod supported classification as Streptococcus mitis subsp. mitis. Genomic analysis identified a 109-amino-acid qacG homolog predicted to encode a small multidrug resistance (SMR)-family efflux transporter. The locus was located near genes associated with mobile genetic elements, raising the possibility of horizontal acquisition. The predicted QacG protein retained residues conserved in the extensively characterized SMR transporter EmrE, and RT-qPCR detected qacG transcripts under standard culture conditions. Nevertheless, Picklauza did not display increased tolerance to benzalkonium chloride, benzethonium chloride, or ethidium bromide compared with S. mitis NCTC 12261. Picklauza also differed from the reference strain in growth kinetics, carbon utilization, and antimicrobial susceptibility. PCR screening detected qacG homologs in three additional oral isolates from patients with IPF. Together, these findings identify a transcriptionally active, putatively mobile qacG homolog in oral streptococci while revealing a disconnect between gene carriage and QAC susceptibility under the conditions tested. This work highlights the need to validate predicted resistance determinants phenotypically and to investigate the mobility and conditional activity of SMR-family genes across genus boundaries in host-associated microbial communities.

microbiology↗

bioRxiv2024

Dendritic Cell - Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHR{Delta}ex2) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHR{Delta}ex2 mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

immunology↗

bioRxiv2019

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.\n\nObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.\n\nMethods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.\n\nMain resultsWe identified and replicated three new genome-wide significant (P<5x10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.\n\nConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

genomics↗