Daily Respiratory Research Analysis

The transcriptional repressor FOXN3 plays a key role in regulating pulmonary inflammatory responses, which are crucial in the development of pulmonary fibrosis. However, its specific regulatory function in lung fibrosis remains unclear. Here, we show that FOXN3 suppresses pulmonary fibrosis by inhibiting Smad transcriptional activity. FOXN3 targets a substantial number of Smad response gene promoters, facilitating Smad4 ubiquitination, which disrupts the association of the Smad2/3/4 complex with chromatin and abolishes its transcriptional response. In response to pro-fibrotic stimuli, NEK6 phosphorylates FOXN3 at S412 and S416, leading to its degradation. The loss of FOXN3 inhibits β-TrCP-mediated ubiquitination of Smad4, stabilizing the Smad complex's association with its responsive elements and promoting transcriptional activation, thus contributing to the development of pulmonary fibrosis. Notably, we found a significant inverse expression pattern between FOXN3 and Smad4 in clinical pulmonary fibrosis cases, underscoring the importance of the NEK6-FOXN3-Smad axis in the pathological process of pulmonary fibrosis.

BACKGROUND: Intranasal vaccines against respiratory viruses are desired due to ease of administration and potential to protect against virus infection of the upper respiratory tract. METHODS: We tested a cationic liposomal adjuvant delivering the TLR3 agonist Poly (I:C) (CAF®09b) for intranasal administration, by formulating this with SARS-CoV-2 spike trimeric protein and assessing airway mucosal immune responses in mice. The vaccine was further evaluated in SARS-CoV-2 virus challenge models, using mice expressing the human ACE2 receptor and Syrian hamsters. FINDINGS: The intranasal vaccine elicited both serum neutralising antibody responses and IgA responses in the upper respiratory tract. Uniquely, it also elicited high-magnitude CD4 and CD8 T cell responses in the lung parenchyma and nasal-associated lymphoid tissue. In contrast, parenteral administration of the same vaccine, or the mRNA-1273 (Spikevax®) vaccine, led to systemic antibody responses and vaccine-induced CD4 T cells were mainly found in circulation. The intranasal vaccine protected against homologous SARS-CoV-2 (Wuhan-Hu-1) challenge in K18-hACE2 mice, preventing weight loss and virus infection in the upper and lower airways. In Syrian hamsters, the vaccine prevented weight loss and significantly reduced virus load after challenge with the homologous strain and Omicron BA.5. INTERPRETATION: This study demonstrates that intranasal subunit vaccines containing TLR3-stimulating cationic liposomes effectively induce airway IgA and T cell responses, which could be utilised in future viral pandemics. FUNDING: This work was primarily supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.

BACKGROUND: Nirsevimab, a long-acting monoclonal antibody, and RSVpreF, a maternal vaccine, are newly approved respiratory syncytial virus (RSV) prophylactics for infants in Canada. Both have the potential to expand prevention efforts, but there is limited evidence regarding their cost-effectiveness and how it varies across the country, despite disparate hospitalisation rates and resource use among different populations. METHODS: We developed a decision tree model to follow twelve monthly birth cohorts through their first year of life, incorporating risk differentiation based on Canadian region, prematurity, and comorbidities. The model tracked medically attended infections, including hospitalisations, intensive care unit admissions, and outpatient visits, comparing costs (in 2024 Canadian dollars) and effectiveness (in quality-adjusted life years (QALYs)) of nine different immunisation strategies compared to no intervention. The analysis was conducted from both healthcare and societal perspectives. We conducted threshold price analyses, varying the price-per-dose of each product to determine the threshold prices at which expanded coverage becomes cost-effective. RESULTS: At base case prices, the optimal strategy varies by region, but in all cases, the optimal strategy is both cost-saving and more effective than no intervention. In southern Canada, it is optimal to immunise only palivizumab-eligible infants (those born very prematurely or with high-risk comorbidities) with nirsevimab, resulting in cost savings of $4.14 and QALY gains of 0.000022 QALY per infant compared to no intervention. In the Northwest Territories, it is best to expand protection with nirsevimab to include all preterm infants (cost savings of $28.68 and QALY gains of 0.00007 per infant). In Nunavik and Nunavut, immunising all infants under 6 months and all infants under twelve months with nirsevimab are the best strategies, respectively (cost savings of $399.61 and QALY gains of 0.000821 per infant in Nunavik, and cost savings of $1067.03 and QALY gains of 0.000884 per infant in Nunavut). Universal, country-wide immunisation with nirsevimab would require a price-per-dose of under $112 to become the most cost-effective prevention strategy. CONCLUSIONS: The optimal strategy for preventing respiratory syncytial virus disease in Canadian infants depends on product price and regional risk level and resource use. Canadian policy should account for these factors.