Daily Respiratory Research Analysis
Analyzed 86 papers and selected 3 impactful papers.
Summary
Top advances span mechanistic immunometabolism in bacterial pneumonia, a modular intranasal vaccine providing broad sarbecovirus protection, and genetic determinants linking BMI to COPD imaging phenotypes. Together, they highlight pathways for host-directed therapy, pandemic‑ready mucosal immunization, and precision respiratory phenotyping.
Research Themes
- Host immunometabolism and epigenetic regulation in lung infection
- Broad-spectrum intranasal vaccination against ACE2-using sarbecoviruses
- Genetic architecture of COPD imaging phenotypes (emphysema vs airway wall thickening)
Selected Articles
1. Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.
In murine Pseudomonas aeruginosa pneumonia, PHGDH-driven serine synthesis fuels one‑carbon metabolism to amplify macrophage inflammation via H3K27me3–DUSP4 interaction and ERK1/2 activation. Genetic myeloid-specific PHGDH deletion, pharmacologic PHGDH inhibition, and dietary L‑serine restriction each reduced lung injury and bacterial load and improved survival.
Impact: This study uncovers a metabolism–epigenetics axis as a lever to modulate hyperinflammation in bacterial pneumonia and demonstrates actionable targets that improved outcomes in vivo.
Clinical Implications: PHGDH and serine metabolism represent host-directed therapeutic targets to attenuate injurious inflammation in severe Pseudomonas pneumonia, potentially as adjuncts to antibiotics.
Key Findings
- PHGDH inhibition (genetic and pharmacologic) suppressed macrophage hyperactivation and pro-inflammatory cytokine production.
- Myeloid-specific deletion of PHGDH improved survival, alleviated lung injury, and reduced bacterial load in murine P. aeruginosa pneumonia.
- Dietary L-serine restriction improved prognosis in infected mice.
- Mechanistically, PHGDH-driven L-serine synthesis augments one-carbon metabolism, strengthening H3K27me3–DUSP4 interaction and promoting ERK1/2 phosphorylation to amplify inflammation.
Methodological Strengths
- Convergent genetic (myeloid-specific knockout) and pharmacologic inhibition strategies
- Robust in vivo murine pneumonia model with survival, lung injury, and bacterial burden endpoints
- Mechanistic dissection linking metabolism to epigenetic readers and MAPK signaling
Limitations
- Preclinical murine and cell-based data; human translational validity remains to be established
- Potential off-target effects of pharmacologic inhibitors were not fully delineated
- Generalizability across bacterial pathogens and infection contexts not tested
Future Directions: Evaluate PHGDH/serine-pathway inhibitors and dietary modulation in translational models and early-phase trials; validate mechanisms in human macrophages and patient samples; assess synergy with antibiotics.
Metabolic reprogramming in immune cells can determine the outcome of pathogen infection. For Pseudomonas aeruginosa, a clinically challenging pathogen, it remains unclear whether the host can exploit this strategy to combat bacterial invasion. Here, we identify phosphoglycerate dehydrogenase as a key mediator of macrophage inflammation during Pseudomonas aeruginosa infection. Pharmacological and genetic inhibition of phosphoglycerate dehydrogenase suppress macrophage hyperactivation and the production of pro-inflammatory cytokines. In a murine model of Pseudomonas ae
2. A modular three in one mucosal vaccine against three antigenic clusters of ACE2 using sarbecoviruses.
By antigenically clustering sarbecovirus RBDs, the authors engineered a single intranasal 3‑in‑1 immunogen that elicited robust systemic and mucosal immunity and protected mice against Omicron BA.1, WIV1, and lethal rRsSHC014S challenge. The KFD‑adjuvanted formulation suggests a modular, rapidly deployable, broad‑spectrum mucosal vaccine platform.
Impact: Introduces a broadly protective, needle‑free mucosal vaccine concept with demonstrated cross‑sarbecovirus protection, addressing pandemic preparedness for emerging ACE2‑using coronaviruses.
Clinical Implications: If translated to humans, intranasal 3‑in‑1 vaccination could simplify delivery, induce mucosal immunity that may reduce transmission, and provide broad coverage against current and future sarbecoviruses.
Key Findings
- Antigenic mapping identified three distinct sarbecovirus RBD clusters guiding immunogen design.
- A single engineered 3Rs‑NC immunogen with KFD adjuvant induced high RBD‑specific serum IgG and mucosal IgA with potent neutralization.
- Intranasal vaccination protected both upper and lower airways against Omicron BA.1 and WIV1 and conferred protection from lethal rRsSHC014S challenge.
- Sex‑dependent efficacy was observed, with more efficient protection in female mice.
Methodological Strengths
- Data‑driven antigenic clustering informing immunogen engineering
- Demonstration of mucosal and systemic immunity with functional protection across multiple sarbecoviruses, including lethal challenge
- Use of a clinically relevant mucosal adjuvant candidate (flagellin‑derived KFD)
Limitations
- Findings are limited to murine models; human immunogenicity, durability, and safety remain unknown
- Manufacturing scalability and stability of multi‑RBD constructs require validation
- Regulatory pathway for KFD adjuvant and intranasal delivery needs clarification
Future Directions: Advance to translational studies assessing dose, schedule, durability, and transmission impact in larger animals and phase 1 trials; dissect correlates of protection and sex differences.
The recurrent emergence of ACE2‑using sarbecovirus underscores the need for a broadly protective vaccine. Here, we mapped the antigenic landscape of sarbecovirus receptor-binding domains (RBDs) and identified three distinct clusters. We then engineered a single "three‑in‑one" immunogen, 3Rs-NC, incorporating representative RBDs from each cluster into a single scaffold. Intranasal administration of 3Rs-NC with a flagellin-derived mucosal adjuvant (KFD), which possess excellent safety profile potential for clinical usage, elicited high titers of RBD-specific serum IgG and mucosal IgA, as well as potent neutralizing antibody responses in mice. Furthermore, KFD-adjuvanted 3Rs-NC conferred sustained protection in both the upper and lower respiratory tracts against SARS-CoV-2 Omicron BA.1 and SARS-like coronavirus WIV1. Additionally, 3Rs-NC immunization protected mice from lethal challenge of SARS-like coronavirus rRsSHC014S, with more efficient protection observed in female mice than male mice. This needle-free formulation offers a potent, broad-spectrum vaccine candidate against current and emerging ACE2-using sarbecoviruses, functioning as a modular "three-in-one" vaccine platform ready for rapid deployment in future coronavirus outbreaks.
3. BMI-Related Genetic Factors and COPD Imaging Phenotypes.
Across 16,349 participants in COPD-enriched and community cohorts, a higher BMI polygenic score was associated with less CT‑quantified and visually assessed emphysema but greater airway wall thickness. Findings support a genetic basis for differential COPD imaging phenotypes linked to BMI predisposition.
Impact: Clarifies how BMI genetic predisposition relates to emphysema versus airway disease on CT, advancing mechanistic understanding and precision phenotyping in COPD.
Clinical Implications: Genetic BMI risk may inform COPD subtyping and risk stratification (emphysema‑predominant vs airway‑predominant), guiding imaging interpretation and potentially personalized management strategies.
Key Findings
- Each SD increase in BMI polygenic score was associated with less CT emphysema (lower log LAA‑950; higher 15th percentile density; both P<0.0001).
- Higher BMI polygenic score was associated with increased airway wall thickness (Pi10 and segmental wall area percent; P≤0.0013).
- Visual assessments paralleled quantitative CT: reduced emphysema risk and increased airway wall thickening with higher BMI genetic risk.
- Associations were consistent across COPD‑enriched and community cohorts in meta‑analysis (n=16,349).
Methodological Strengths
- Large combined sample across COPD-enriched and community cohorts with meta-analysis
- Use of both quantitative CT metrics and visual interpretation to validate associations
Limitations
- Observational design cannot establish causality; polygenic score captures predisposition not modifiable risk
- Clinical outcomes and treatment responses were not assessed
Future Directions: Integrate BMI genetic risk with multi‑omics and longitudinal outcomes to refine COPD subtypes and predict progression and therapy response.
RATIONALE: While low BMI is associated with emphysema and obesity is associated with airway disease in COPD, the underlying mechanisms are unclear. OBJECTIVES: To examine the association between BMI-related genetic variants and emphysema and airway disease imaging phenotypes. METHODS: We aggregated genetic variants from population-based genome-wide association studies to generate a polygenic score of BMI (PGSBMI). We examined associations of the PGSBMI with automated quantification and visual interpretation of computed tomographic emphysema and airway wall thickness (AWT) in COPD-enriched and community-based cohorts. We summarized the results using meta-analysis. MEASUREMENTS AND MAIN RESULTS: In the meta-analyses combining results of all cohorts (n = 16,349), a standard-deviation increase of the PGSBMI was associated with less emphysema as quantified by log-transformed percent of low attenuation areas ≤950 Hounsfield units (β = -0.062, P <0.0001) and 15th percentile value of lung density histogram (β = 2.27, P <0.0001), and increased AWT as quantified by the square root of wall area of a 10-mm lumen perimeter airway (β = 0.016, P = 0.0006) and mean segmental bronchial wall area percent (β = 0.26, P = 0.0013). For imaging characteristics assessed by visual interpretation, a higher PGSBMI was associated with reduced emphysema in both COPD-enriched cohorts (OR for a higher severity grade = 0.89, P = 0.0080) and in the community-based Framingham Heart Study (OR for the presence of emphysema = 0.82, P = 0.0034), and a higher risk of airway wall thickening in the COPDGene study (OR = 1.17, P = 0.0023). CONCLUSIONS: In individuals with and without COPD, a higher BMI polygenic risk is associated with both quantitative and visual decreased emphysema and increased AWT, suggesting genetic determinants of BMI affect both emphysema and airway wall thickening.