Biology subjects

O'Dwyer, D. N.

Publications and source records attributed to O'Dwyer, D. N..

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

Lung Microbiome Intervention Attenuates Herpesvirus-Induced Post-HCT Pulmonary Fibrosis Through PD-L1 Upregulation on Dendritic Cells

Alterations in the lung microbiome frequently accompany adverse pulmonary outcomes. Hematopoietic cell transplantation (HCT) markedly affects the lung microbiome corresponding with a high incidence of post-HCT pulmonary complications. In a preclinical mouse model of HCT, we observed a reduction in Lactobacillus johnsonii within the lung microbiome following transplantation. Intranasal administration of live or heat-killed (HK) L. johnsonii at low doses reduced gammaherpesvirus-induced pulmonary fibrosis in HCT mice, in which IL-17A plays an essential role. HK L. johnsonii treatment of HCT mice suppressed inflammatory cytokine production by lung macrophages and decreased Il17a expression in T helper 17 (Th17) cells. HK L. johnsonii increased PD-L1 expression on the surface of type II conventional dendritic cells (cDC2) in HCT mice and in vitro in bone marrow-derived dendritic cells (BMDCs). HK L. johnsonii-exposed BMDCs also inhibited IL-17A secretion from co-cultured Th17 cells in a PD-1-dependent manner. Notably, when HK L. johnsonii was administered to HCT mice reconstituted with bone marrow cells from PD-1 knockout (KO) mice, which lack a PD-L1 mediated response, HK L. johnsonii-mediated reduction of pulmonary fibrosis was negated. Collectively, our findings demonstrate that HK L. johnsonii mitigates herpesvirus-induced pulmonary fibrosis in HCT mice by modulating cDC2 surface expression of PD-L1, which subsequently suppresses Il17a expression in Th17 cells, pointing towards a potential postbiotic-based strategy for immunomodulation to address pulmonary complications of HCT.

immunology↗

bioRxiv2024

Toll-Like-Receptor 5 protects against pulmonary fibrosis by reducing lung dysbiosis

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to epithelial injury and experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analogue protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury. In contrast, TLR5 deficiency in mice and IPF patients is associated with lung dysbiosis. Elimination of the microbiome in mice through antibiotics abolishes the protective effect of TLR5 and reconstitution of the microbiome rescues the observed phenotype. In aggregate, TLR5 deficiency is associated with IPF and dysbiosis in humans and in the murine model of pulmonary fibrosis. Furthermore, TLR5 protects against pulmonary fibrosis in mice and this protection is mediated by effects on the microbiome. One-sentence summaryDeficiency in the innate immune receptor TLR5 is a risk factor for pulmonary fibrosis, because TLR5 prevents microbial dysbiosis after lung injury.

immunology↗