Daily Respiratory Research Analysis
Three papers stood out today across basic, translational, and clinical respiratory research: (1) discovery of a secreted antibacterial endopeptidase (CwhA) from Aspergillus fumigatus that cleaves Gram-positive peptidoglycan and may reshape lung co-infections and host responses; (2) multi-cohort evidence that COPD comorbidity in lung adenocarcinoma correlates with a more immunogenic tumor microenvironment and better immunotherapy responses; and (3) population-based proteomics identifying novel ci
Summary
Three papers stood out today across basic, translational, and clinical respiratory research: (1) discovery of a secreted antibacterial endopeptidase (CwhA) from Aspergillus fumigatus that cleaves Gram-positive peptidoglycan and may reshape lung co-infections and host responses; (2) multi-cohort evidence that COPD comorbidity in lung adenocarcinoma correlates with a more immunogenic tumor microenvironment and better immunotherapy responses; and (3) population-based proteomics identifying novel circulating proteins and pathways associated with CT-quantified emphysema, replicated in COPD cohorts.
Research Themes
- Cross-kingdom microbe–immune interactions in lung disease
- COPD comorbidity shaping tumor immunogenicity and immunotherapy response
- Proteomic biomarkers and pathways of emphysema in population cohorts
Selected Articles
1. Identification of a fungal antibacterial endopeptidase that cleaves peptidoglycan.
This study identifies CwhA, the first secreted antibacterial endopeptidase from Aspergillus fumigatus, which cleaves Gram-positive peptidoglycan, causing lysis and releasing immunostimulatory fragments. CwhA is induced by bacteria and abundant in murine lungs during invasive aspergillosis; its cleavage products stimulate human immune cell cytokine production, indicating a cross-kingdom factor that could modulate co-infections and host responses in the lung.
Impact: Reveals a previously unknown fungal weapon against bacteria with direct relevance to lung co-infections and immune modulation in invasive aspergillosis.
Clinical Implications: While preclinical, CwhA suggests that fungal–bacterial interactions may influence infection severity and immune responses in the lung. Targeting or harnessing CwhA or its pathways could inform adjunctive therapies to manage bacterial co-infections in invasive aspergillosis.
Key Findings
- Identified CwhA, a secreted A. fumigatus endopeptidase that cleaves Gram-positive peptidoglycan at specific stem peptide residues, leading to bacterial lysis.
- cwhA expression is induced by bacterial presence, and CwhA is abundant in murine lungs during invasive pulmonary aspergillosis.
- CwhA-generated peptidoglycan fragments stimulate cytokine production in human immune cells in vitro, indicating immunomodulatory potential.
Methodological Strengths
- Multi-modal evidence including biochemical characterization, bacterial lysis assays, and abundance in murine lungs during disease.
- Demonstration of functional immunostimulation by CwhA-generated peptidoglycan fragments in human immune cells.
Limitations
- Lacks in vivo co-infection models directly linking CwhA activity to clinical outcomes in lungs.
- No human clinical data demonstrating microbiome shifts or outcome modification.
Future Directions: Test CwhA in in vivo co-infection models, define structural determinants and specificity, and explore therapeutic inhibition or exploitation of CwhA to modulate bacterial co-infections and host inflammation in aspergillosis.
Aspergillus fumigatus is a saprophytic fungus dwelling in soil and on decaying plant material, but also an opportunistic pathogen in immunocompromised patients. In its environmental niche, A. fumigatus faces competition from other microorganisms including bacteria. Here, we describe the discovery of the first secreted antibacterial protein in A. fumigatus. We identify a secreted fungal endopeptidase, designated CwhA, that cleaves peptidoglycan of Gram-positive bacteria at specific residues within the peptidoglycan stem peptide. Cleavage leads to bacterial lysis and the release of peptidoglycan cleavage products. Expression of cwhA is induced by the presence of bacteria. Furthermore, CwhA is highly abundant in murine lungs during invasive pulmonary aspergillosis and peptidoglycan cleavage products generated by CwhA stimulate cytokine production of human immune cells in vitro. Although CwhA does not affect human cells directly, this novel player in fungal-bacterial interactions could affect A. fumigatus infections by inhibiting Gram-positive bacteria in its vicinity, and possibly modulate the immune system.
2. Enhanced immunotherapy response in lung adenocarcinoma patients with COPD: insights into tumor cells and immune microenvironment characteristics.
Across a 248-patient immunotherapy cohort and multi-modal validation, COPD-associated LUAD showed higher HLA-I expression on malignant cells, a less aggressive tumor phenotype, and a more active immune microenvironment with increased cytotoxic infiltration. These features correlated with improved immunotherapy responses, positioning COPD status as a clinically relevant stratifier.
Impact: Provides mechanistic and clinical evidence that COPD comorbidity confers a more immunogenic LUAD phenotype with better immunotherapy outcomes, informing precision treatment strategies.
Clinical Implications: COPD status may serve as a positive predictive factor for immunotherapy in LUAD and supports integrating COPD assessment into treatment decision-making and trial stratification.
Key Findings
- In a 248-patient LUAD immunotherapy cohort, COPD comorbidity associated with improved immunotherapy responses.
- Single-cell RNA-seq (187,123 cells) and mfIHC showed higher HLA-I expression on malignant cells and increased NK and effector T-cell infiltration in COPD-associated tumors.
- An independent 65-patient immunotherapy cohort supported these findings, indicating a robust, multi-cohort signal.
Methodological Strengths
- Multi-cohort design integrating clinical outcomes with scRNA-seq and mfIHC.
- Independent validation cohort and orthogonal assays strengthen reproducibility.
Limitations
- Single-cell discovery set included only six treatment-naïve patients (three COPD, three non-COPD).
- Observational design with potential residual confounding; no randomized assignment to immunotherapy.
Future Directions: Prospective trials stratifying by COPD status, mechanistic dissection of HLA-I regulation in COPD-LUAD, and biomarker development for patient selection.
BACKGROUND: Lung cancer and chronic obstructive pulmonary disease (COPD) are major global health challenges, and their coexistence in patients presents unique clinical complexities. Interestingly, patients with both lung adenocarcinoma (LUAD) and COPD show reduced responses to conventional chemotherapy and targeted therapies but demonstrate enhanced sensitivity to immunotherapy. METHODS: We investigated this phenomenon using a cohort of 248 LUAD patients undergoing immunotherapy. Single-cell transcriptomic analysis was performed on 187,123 cells from tumor samples, adjacent normal tissues, and peripheral blood mononuclear cells from six treatment-naïve LUAD patients—three with COPD and three without. To further validate these findings, we conducted multiplex fluorescent immunohistochemical (mfIHC) analysis on 34 additional treatment-naïve LUAD patients and analyzed an independent cohort of 65 LUAD patients undergoing immunotherapy. RESULTS: We found that COPD-associated LUAD tumors exhibited distinctive features, including elevated expression of human leukocyte antigen I (HLA-I) on malignant cells and a less aggressive tumor phenotype. The immune microenvironment in these tumors was more active, with increased infiltration of NK cells, effector CD4 CONCLUSION: Our study reveals that COPD leads to elevated HLA-I expression and a more active immune microenvironment in LUAD tumors, characterized by enhanced cytotoxic immune cell infiltration and a shift towards immunoregulatory profiles. These features correlate with improved immunotherapy responses, highlighting the potential for optimizing treatment strategies in LUAD patients with COPD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02332-7.
3. Proteomic discovery analysis of quantitatively assessed emphysema in the general population. The MESA Lung Study.
In 2,504 MESA participants with full-lung CT and plasma aptamer profiling, 1,234 proteins associated with percent emphysema; 35 replicated in SPIROMICS and COPDGene. Novel proteins (e.g., FAM177A1, syntenin-2, UCHL25, C20orf173) and enriched pathways (chemokine regulation, cell–cell adhesion, RAGE signaling) highlight mechanisms and potential therapeutic targets.
Impact: Provides replicated, pathway-anchored proteomic signatures of emphysema in a general population, advancing biomarker discovery and mechanistic understanding beyond airflow limitation.
Clinical Implications: Circulating proteins linked to CT-quantified emphysema could guide risk stratification, early detection, and therapeutic target development; external validation in diverse clinical settings and longitudinal prediction is the next step.
Key Findings
- In MESA (n=2,504), 1,234 plasma aptamers were significantly associated with percent emphysema; 35 proteins replicated in SPIROMICS and COPDGene.
- Novel associations included FAM177A1, syntenin-2, UCHL25, and C20orf173 alongside established markers like sRAGE and S100A12.
- GO/Reactome enrichment implicated chemokine regulation, cell–cell adhesion, and RAGE signaling pathways.
Methodological Strengths
- Population-based, multiethnic cohort with CT quantification and high-dimensional proteomics.
- Independent replication in two COPD cohorts and pathway enrichment analyses supporting biological plausibility.
Limitations
- Cross-sectional design limits causal inference and prognostic utility without longitudinal validation.
- Replication count (35 proteins) is modest relative to discovery; potential platform-specific biases.
Future Directions: Longitudinal validation for incident outcomes, mechanistic follow-up of novel proteins, and translation into clinical assays for risk prediction and therapy development.
BACKGROUND: Pulmonary emphysema occurs frequently in older adults, often without airflow limitation. Its presence predicts symptoms, respiratory hospitalizations and deaths, and all-cause mortality. Proteomics may provide further insights into emphysema pathogenesis and inform therapeutic targets. OBJECTIVE: We performed a proteomic discovery analysis of percent emphysema on computed tomography (CT) in a population-based, multiethnic sample from the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Replication was performed in two chronic obstructive pulmonary disease (COPD)-based studies, the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) and the Genetic Epidemiology of COPD (COPDGene) Study. METHODS: MESA recruited participants from the general population in 2000-02. The MESA Lung Study performed full-lung CT scans in 2010-12. Percent emphysema was defined as the percentage of lung voxels < -950 Hounsfield units. Over 7,200 plasma aptamers were measured via SomaScan. Cross-sectional linear and least absolute shrinkage and selection operator (LASSO) regression models were adjusted for demographics, anthropometrics, smoking, renal function, and scanner parameters. Statistical significance was defined as a false discovery rate p-value < 0.05. Gene Ontology (GO)/Reactome enrichment analyses were performed. LASSO-selected proteins' predictive performance was evaluated. RESULTS: Among 2,504 participants in the MESA Lung Study, mean age was 69.4 years, 1,291 had ever smoked, and median percent emphysema-like lung was 1.4%. In total, 1,234 aptamers were significantly associated with percent emphysema in the MESA Lung Study, and 35 replicated in the SPIROMICS and COPDGene Studies. Novel associations included protein family with sequence similarity (FAM) 177A1, syntenin-2, ubiquitin carboxyl-terminal hydrolase 25, and uncharacterized protein C20orf173. Previously identified emphysema-associated proteins included soluble advanced glycosylation end product-specific receptor (sRAGE), protein S100-A12, high mobility group protein B1, and roundabout homolog 2. Enrichment analyses identified 40 GO biological processes, including chemokine production and regulation and cell-cell adhesion and regulation, and two Reactome pathways, including RAGE signaling. In tenfold cross-validation, novel proteins were largely retained by LASSO (R CONCLUSIONS: This analysis in a general population sample identified novel and previously characterized proteins whose functional roles were validated by GO/Reactome enriched pathways, offering new insights into emphysema pathophysiology and therapeutics.