Daily Respiratory Research Analysis
Three impactful respiratory studies stood out today: a mechanistic Nature Communications paper reveals HKU5 bat merbecoviruses use bat and mustelid ACE2 for entry, sharpening spillover risk assessment; a randomized trial shows esophageal pressure–guided, individualized ventilation improves outcomes in severe acute pancreatitis–related ARDS; and an Advanced Science study uses a human immuno-lung organoid to uncover a THBS1–(ITGA3+ITGB1) axis driving macrophage-mediated lung cell senescence after
Summary
Three impactful respiratory studies stood out today: a mechanistic Nature Communications paper reveals HKU5 bat merbecoviruses use bat and mustelid ACE2 for entry, sharpening spillover risk assessment; a randomized trial shows esophageal pressure–guided, individualized ventilation improves outcomes in severe acute pancreatitis–related ARDS; and an Advanced Science study uses a human immuno-lung organoid to uncover a THBS1–(ITGA3+ITGB1) axis driving macrophage-mediated lung cell senescence after SARS-CoV-2 infection.
Research Themes
- Coronavirus receptor tropism and zoonotic spillover risk
- Individualized mechanical ventilation guided by esophageal pressure in ARDS
- Macrophage-driven lung cell senescence in infectious injury using human immuno-lung organoids
Selected Articles
1. HKU5 bat merbecoviruses engage bat and mink ACE2 as entry receptors.
Using pseudotyped and full-length virus systems, the authors demonstrate that HKU5 merbecoviruses utilize bat (Pipistrellus abramus) ACE2, and also bind mustelid (American mink, stoat) ACE2, but not human ACE2 or DPP4. Cryo-EM reveals a distinct spike–ACE2 interface, and MERS-CoV vaccine sera poorly neutralize HKU5, informing pan-merbecovirus vaccine strategy and surveillance priorities.
Impact: It uncovers a new receptor usage pattern for merbecoviruses with structural validation, directly informing zoonotic risk, host range prediction, and pan-merbecovirus vaccine design.
Clinical Implications: While not immediately changing clinical practice, these results prioritize surveillance of mustelids and bats, guide receptor-focused risk assessments, and suggest current MERS vaccines may not cross-protect against HKU5-like viruses.
Key Findings
- HKU5 uses Pipistrellus abramus ACE2, but not human ACE2 or DPP4, for entry (pseudotyped and full-length virus).
- Cryo-EM and mutagenesis define a spike–ACE2 interaction distinct from other ACE2-using coronaviruses.
- HKU5 also engages ACE2 from American mink and stoat, identifying mustelids as potential intermediate hosts.
- MERS-CoV vaccine sera poorly neutralize HKU5, indicating limited cross-protection.
Methodological Strengths
- Use of both pseudotyped and authentic full-length virus systems to validate receptor usage.
- High-resolution cryo-EM structural analysis with structure-guided mutagenesis.
Limitations
- Human infectivity remains unproven as human ACE2 is not used.
- In vivo animal transmission or pathogenesis data were not presented.
Future Directions: Evaluate in vivo host range and transmission in mustelid models, assess cross-species adaptation potential, and develop pan-merbecovirus immunogens targeting conserved spike epitopes.
2. Individualized Lung-Protective Ventilation Strategy Based on Esophageal Pressure Monitoring in Patients With ARDS Associated With Severe Acute Pancreatitis-A Randomized Controlled Trial.
In a single-center RCT of 124 SAP-related ARDS patients, esophageal pressure–guided individualized ventilation reduced transpulmonary pressures and driving pressures, improved compliance and oxygenation, shortened ventilation and ICU stay, and reduced VAP and 28-day mortality versus conventional lung-protective ventilation. ΔPL at 72 h independently predicted 28-day mortality (AUC 0.832).
Impact: This RCT provides actionable evidence that esophageal pressure–guided ventilation improves hard outcomes, including mortality, in a high-risk ARDS subgroup.
Clinical Implications: Consider implementing esophageal pressure monitoring to individualize PEEP/VT settings in SAP-related ARDS; monitor ΔPL at 72 h as a prognostic marker to stratify risk and guide therapy.
Key Findings
- Transpulmonary pressure, transpulmonary driving pressure (ΔPL), and driving pressure were significantly lower with esophageal pressure–guided ventilation.
- Static compliance and PaO2/FiO2 were significantly higher in the EPM-guided group.
- EPM guidance reduced duration of mechanical ventilation, ICU length of stay, VAP incidence, and 28-day mortality.
- ΔPL at 72 h independently predicted 28-day mortality (AUC 0.832).
Methodological Strengths
- Randomized controlled design with comprehensive physiological and clinical endpoints.
- Multivariable regression and ROC analyses to identify and validate prognostic markers (ΔPL).
Limitations
- Single-center study with potential limits on generalizability.
- Blinding was not described; long-term outcomes beyond 28 days were not reported.
Future Directions: Multicenter RCTs to confirm generalizability; evaluate protocolized ΔPL targets and integration with adjunctive ARDS strategies; assess long-term functional outcomes.
3. A Human Immuno-Lung Organoid Model to Study Macrophage-Mediated Lung Cell Senescence Upon SARS-CoV-2 Infection.
Human immuno-lung organoids (hPSC-derived alveolar/airway organoids co-cultured with macrophages) and spatial transcriptomics show that proinflammatory macrophages drive lung cell senescence via THBS1–(ITGA3+ITGB1) signaling after SARS-CoV-2 infection. The model provides a physiologically relevant platform to study immune-mediated tissue damage.
Impact: It introduces a human immuno-lung organoid co-culture that recapitulates macrophage–epithelium interactions and reveals a previously unrecognized THBS1–integrin pathway driving infection-related lung senescence.
Clinical Implications: The THBS1–(ITGA3+ITGB1) axis emerges as a candidate target to mitigate post-infectious lung injury and senescence; the organoid platform can accelerate preclinical testing of senescence-modulating and anti-inflammatory therapeutics.
Key Findings
- Spatial transcriptomics of human lung tissues identified proinflammatory macrophage activation in COVID-19 explants.
- A human immuno-lung organoid co-culture (hPSC-derived alveolar/airway organoids + macrophages) was established to model immune-mediated damage.
- Proinflammatory macrophages induced lung cell senescence via the THBS1–(ITGA3+ITGB1) signaling axis, validated by spatial transcriptomics.
Methodological Strengths
- Integration of human explant/autopsy spatial transcriptomics with a physiologically relevant co-culture organoid system.
- Mechanistic pathway validation (THBS1–integrin axis) across complementary platforms.
Limitations
- In vitro organoid findings require in vivo validation of senescence relevance and therapeutic modulation.
- Quantitative dose–response and intervention studies were not detailed in the abstract.
Future Directions: Test THBS1–integrin blockade in preclinical models of post-viral lung injury; expand organoid co-cultures with adaptive immune components; map senescence heterogeneity across infectious contexts.