Weekly Respiratory Research Analysis
This week’s respiratory literature emphasizes zoonotic risk, mechanistic host targets, and pragmatic clinical trials. A bat merbecovirus that uses human ACE2 and infects human organoids elevates spillover concern and pandemic preparedness priorities. Mechanistic studies (kinase and cytokine signaling) identify druggable host pathways for fibrosis and broad respiratory-virus replication, while large RCTs and guideline updates inform ICU diagnostics and management strategies. Implementation and po
Summary
This week’s respiratory literature emphasizes zoonotic risk, mechanistic host targets, and pragmatic clinical trials. A bat merbecovirus that uses human ACE2 and infects human organoids elevates spillover concern and pandemic preparedness priorities. Mechanistic studies (kinase and cytokine signaling) identify druggable host pathways for fibrosis and broad respiratory-virus replication, while large RCTs and guideline updates inform ICU diagnostics and management strategies. Implementation and policy papers address RSV prevention rollout, vaccine/antibody economics, and real-world uptake.
Selected Articles
1. Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor.
A lineage‑2 HKU5 merbecovirus from bats efficiently uses human ACE2 with a distinct RBD–ACE2 binding mode and infects hACE2 cell lines as well as human respiratory and enteric organoids, indicating broad tropism and elevated zoonotic spillover risk. Structural cryo‑EM and authentic‑virus assays underpin the finding.
Impact: First demonstration that an HKU5 merbecovirus lineage uses human ACE2 and infects human organoids, directly raising zoonotic risk and informing surveillance, receptor screening, and countermeasure prioritization.
Clinical Implications: Prioritize functional surveillance of merbecoviruses, include HKU5‑like viruses in spillover risk assessments, and accelerate countermeasure research (vaccines, antivirals) that consider ACE2‑using coronaviruses.
Key Findings
- HKU5‑CoV lineage 2 efficiently utilizes human ACE2 as an entry receptor.
- Cryo‑EM reveals a distinct RBD–ACE2 binding footprint overlapping features of ACE2‑using sarbecoviruses and NL63.
- Authentic HKU5‑CoV‑2 infects hACE2‑expressing cell lines and human respiratory and enteric organoids, indicating broad tissue tropism.
2. Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling.
This mechanistic study shows FOXN3 suppresses Smad‑mediated profibrotic transcription by promoting Smad4 ubiquitination; NEK6 phosphorylates and degrades FOXN3 in response to profibrotic stimuli, stabilizing Smad4 and driving fibrosis. Clinical samples show inverse FOXN3/Smad4 expression, supporting translational relevance.
Impact: Reveals a kinase‑regulated checkpoint (NEK6→FOXN3→Smad) amenable to pharmacologic intervention; opens a new, actionable path for antifibrotic drug development and biomarker research in pulmonary fibrosis.
Clinical Implications: Supports preclinical testing of NEK6 inhibitors or FOXN3‑stabilizing strategies and evaluation of FOXN3/Smad4 expression as biomarkers to stratify patients or monitor response in IPF trials.
Key Findings
- FOXN3 inhibits Smad transcriptional activity by promoting Smad4 ubiquitination and disrupting Smad2/3/4 chromatin binding.
- NEK6 phosphorylates FOXN3 at S412/S416 under profibrotic stimuli, triggering FOXN3 degradation and releasing Smad-driven transcription.
- Clinical fibrosis samples show inverse FOXN3 and Smad4 expression, supporting translational relevance.
3. INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia.
A pragmatic multicenter RCT (n=554) found in‑ICU syndromic PCR increased appropriate and proportionate antibiotic prescribing at 24 hours (76.5% vs 55.9%; +21%) compared with standard care, but failed to demonstrate non‑inferiority for 14‑day clinical cure. Secondary outcomes trended toward control without clear significance, highlighting stewardship gains but unresolved clinical‑effectiveness questions.
Impact: High‑quality pragmatic RCT directly quantifying stewardship benefits of rapid molecular diagnostics in ICU pneumonia and exposing the gap between early diagnostic-driven prescribing and demonstrated clinical cure.
Clinical Implications: Rapid syndromic PCR can be adopted to improve early antibiotic appropriateness in HAP/VAP, but programs must monitor patient outcomes, standardize prescribing guidance, and pursue further effectiveness trials before de‑escalation strategies are broadly mandated.
Key Findings
- At 24 h, appropriate and proportionate antibiotic use was 76.5% with rapid PCR vs 55.9% with standard care (difference 21%; 95% CI 13–28%).
- 14‑day clinical cure did not meet non‑inferiority (56.7% intervention vs 64.5% control; difference −6%, 95% CI −15 to 2%).
- Secondary outcomes (mortality, ΔSOFA) slightly favored control without clear statistical significance.