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.
Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.
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.
BACKGROUND AND OBJECTIVE: Acute respiratory distress syndrome (ARDS) secondary to severe acute pancreatitis (SAP) presents significant management challenges with high mortality rates. This study aimed to investigate the application value of an individualized lung-protective ventilation strategy guided by esophageal pressure (Pes) monitoring in patients with ARDS associated with SAP. METHODS: This randomized controlled trial included 124 patients with SAP-related ARDS admitted to our hospital from January 2023 to December 2023, and they were randomized to a conventional lung protective ventilation group (conventional group, n = 62) and an esophageal pressure monitoring-guided group (EPM-guided group, n = 62). The conventional group adopted a conventional lung protective ventilation strategy; whereas, the EPM-guided group received the individualized ventilation strategy based on EPM. The EPM indicators, respiratory mechanics parameters, oxygenation indicators, and clinical outcomes were compared between the two groups. RESULTS: After treatment, the EPM-guided group showed significantly lower transpulmonary pressure (PL) [(16.82 ± 2.46) versus. (22.41 ± 3.23) cmH2O, p = 0.006], transpulmonary driving pressure (ΔPL) [(12.36 ± 1.83) versus. (16.52 ± 2.37) cmH2O, p = 0.007], and driving pressure (ΔP) [(11.43 ± 1.83) versus. (14.52 ± 2.24) cmH2O, p = 0.008] than the conventional group, whereas static compliance (Cst) [(37.82 ± 4.46) versus. (29.41 ± 5.23) mL/cmH2O, p = 0.009] and the PaO2/FiO2 ratio [(268.82 ± 32.46) versus. (195.41 ± 28.23) mmHg, p = 0.008] were significantly higher. The EPM-guided group had shorter mechanical ventilation duration [(12.32 ± 3.24) versus. (16.83 ± 4.52) d, p = 0.013] and intensive care nit (ICU) length of stay [(18.53 ± 4.62) versus. (23.72 ± 5.83) d, p = 0.018] compared to the conventional group, along with a lower VAP incidence (14.52% vs. 25.81% and p = 0.038) and a 28-day mortality rate (19.35% vs. 32.26% and p = 0.042). Multivariate logistic regression analysis showed that ΔPL at 72 h (OR 1.56, 95% CI 1.25-2.01, p < 0.001) was an independent predictor of a 28-day mortality rate. ROC curve analysis showed that ΔPL had a good diagnostic value for predicting a 28-day mortality rate (AUC = 0.832 and 95% CI 0.760-0.904). Correlation analysis showed that ΔPL at 72 h was significantly negatively correlated with the PaO2/FiO2 ratio (r = -0.71 and p < 0.001) and static compliance (r = -0.69 and p < 0.001). CONCLUSION: Individualized lung protective ventilation strategy guided by EPM can more accurately assess the actual lung inflation pressure, optimize the setting of ventilation parameters, and improve clinical outcomes of patients with SAP-related ARDS.
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.
While COVID-19 affects multiple organ systems, the human respiratory system is the primary viral target and main site for disease progression. In this study, spatial transcriptional assays (NanoString CosMx) are utilized to analyze both explant and autopsy samples from non-COVID and COVID-19 lungs, identifying the activation of proinflammatory macrophages in COVID-19 explants. It is further developed immuno-lung organoids comprising hPSC-derived alveolar and airway organoids co-cultured with macrophages to investigate the impact and underlying mechanisms of macrophage-mediated lung damage following SARS-CoV-2 infection. The findings demonstrate that proinflammatory macrophages induce lung cell senescence through the THBS1-(ITGA3+ITGB1) signaling axis, a mechanism further validated using spatial transcriptomics. This study not only establishes physiologically relevant immuno-lung organoid models for modeling macrophage-mediated tissue damage, but also identifies a previous unrecognized role of the THBS1-(ITGA3+ITGB1) pathway in driving lung cell senescence during infectious disease.