Daily Respiratory Research Analysis
Three impactful respiratory studies span antiviral discovery, diagnostic innovation, and mucosal immunology. A JCI study identifies HGS as a druggable host factor for pan-coronavirus assembly and proposes riboflavin tetrabutyrate as a repurposed inhibitor. Separately, dynamic chest radiography shows promise as a low-radiation alternative to PFTs for COPD screening, and Nature Communications reveals persistent neutrophilic nasal inflammation driving pneumococcal colonization in ART-treated HIV.
Summary
Three impactful respiratory studies span antiviral discovery, diagnostic innovation, and mucosal immunology. A JCI study identifies HGS as a druggable host factor for pan-coronavirus assembly and proposes riboflavin tetrabutyrate as a repurposed inhibitor. Separately, dynamic chest radiography shows promise as a low-radiation alternative to PFTs for COPD screening, and Nature Communications reveals persistent neutrophilic nasal inflammation driving pneumococcal colonization in ART-treated HIV.
Research Themes
- Host-targeted broad-spectrum antivirals for coronaviruses
- Imaging-based functional diagnostics for COPD
- Mucosal immune dysregulation and bacterial colonization in HIV
Selected Articles
1. Targeting the host factor HGS-viral membrane protein interaction in coronavirus infection.
A genome-wide CRISPRi screen identified HGS as essential for coronavirus assembly via direct interaction with the M protein, enabling ERGIC trafficking. HGS-targeting peptides and riboflavin tetrabutyrate disrupted this interaction, blocking virion assembly and demonstrating broad anti-coronavirus activity in vitro and in vivo.
Impact: This work reveals a conserved, druggable host-virus interface and provides a repurposed compound with in vivo efficacy, opening a host-directed antiviral modality with pandemic relevance.
Clinical Implications: Although preclinical, targeting HGS could yield broad-spectrum therapeutics less prone to resistance than viral protein inhibitors. Riboflavin tetrabutyrate merits pharmacokinetic/toxicity profiling and early-phase trials for coronavirus diseases.
Key Findings
- HGS directly binds coronavirus M protein to enable ERGIC trafficking and virion assembly; HGS deficiency retains M in ER and blocks assembly.
- M-derived peptides and riboflavin tetrabutyrate (RTB) bind HGS, disrupt HGS–M interaction, and prevent virion assembly.
- Agents targeting HGS demonstrated broad anti-pan-coronavirus activity in vitro and in vivo.
Methodological Strengths
- Genome-wide CRISPRi screening with mechanistic validation across in vitro and in vivo systems
- Large-scale drug repurposing screen (>5,000 FDA-approved compounds) plus rational peptide design
Limitations
- Preclinical study; human safety, pharmacokinetics, and optimal dosing are unknown
- Host-target engagement may entail on-target toxicity; off-target effects of RTB need evaluation
Future Directions: Advance RTB and peptide inhibitors into ADME/toxicology studies, assess efficacy in relevant animal disease models, and explore combination with direct-acting antivirals to mitigate resistance.
While current antivirals primarily target viral proteins, host-directed strategies remain underexplored. Here, we performed a genome-wide CRISPRi screening to identify the host protein, Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate (HGS), as essential for the pan-coronaviruses infection both in vitro and in vivo. Mechanistically, HGS directly interacts with the viral membrane (M) protein, facilitating its trafficking to the ER-Golgi intermediate compartment (ERGIC) for virion assembly. Conversely, HGS deficiency caused M retention in the ER, blocking assembly. Leveraging this interaction, we designed M-derived peptides and screened over 5,000 FDA-approved drugs, identifying riboflavin tetrabutyrate (RTB). Both the peptides and RTB bind HGS and disrupt its interaction with the M protein, leading to M retention in the ER and subsequent blockade of virion assembly. These agents demonstrated broad anti-pan-coronavirus activity in vitro and in vivo. Collectively, our findings establish HGS as a druggable host target and identify RTB as a promising broad-spectrum antiviral candidate.
2. Dynamic Chest Radiography as an Alternative to Pulmonary Function Tests for Chronic Obstructive Pulmonary Disease.
In a prospective cohort of 553 participants, dynamic chest radiography metrics correlated with PFT indices among COPD patients. Predictive models built with LASSO-logistic regression achieved strong internal performance and yielded a calibrated nomogram, supporting DCR as a potential low-radiation alternative for COPD screening.
Impact: Offers a scalable, low-radiation, imaging-based functional assessment that could expand COPD screening where spirometry is limited.
Clinical Implications: DCR could triage patients for confirmatory PFTs, reduce barriers to COPD detection, and enable longitudinal monitoring where spirometry capacity is constrained.
Key Findings
- Among 553 participants, DCR parameters (e.g., bilateral ΔPLA during deep breathing) correlated with key PFT indices in COPD.
- LASSO-selected DCR features with multivariable logistic regression yielded strong ROC performance on an internal test set.
- A calibrated nomogram visualized COPD probability, supporting clinical interpretability.
Methodological Strengths
- Prospective design with relatively large sample size (n=553) and internal test set
- Multimethod evaluation including correlation analyses, ROC metrics, LASSO feature selection, and calibration
Limitations
- Single-center study with internal validation only; lacks external validation and head-to-head outcome studies
- Abstract truncation limits detailed reporting of specific AUC values and thresholds
Future Directions: Conduct external validation across diverse settings, assess cost-effectiveness and radiation dose optimization, and test DCR-enabled screening pathways on clinical outcomes.
Background Pulmonary function tests (PFTs) are the clinical standard for diagnosing chronic obstructive pulmonary disease (COPD) but face limitations in accessibility and complexity. Dynamic chest radiography (DCR) is an emerging technique that enables dynamic pulmonary function assessment with low radiation exposure, suggesting potential as an alternative to PFTs. However, its diagnostic validity remains unproven. Purpose To determine whether DCR is an efficacious alternative approach to PFTs for COPD screening. Materials and Methods This prospective single-center observational study enrolled participants with or without COPD from November 2022 to July 2024. Correlations between DCR parameters and PFT indexes were assessed using Pearson correlation. Receiver operating characteristic analysis was used to evaluate diagnostic performance. The least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression were used to select features and build and train predictive models, which were tested on an internal test set. A nomogram was used to visualize COPD probability, calibrated using the Hosmer-Lemeshow test. Results This study included 553 participants (median age, 60 years [IQR, 53-67 years]; 355 men; 198 women; 191 with COPD, 362 controls). DCR parameters were positively correlated with PFT indexes in participants with COPD: The combined bilateral (right and left lungs) rate of change in projected lung area (ΔPLA) during deep breathing was correlated with forced expiratory volume in 1 second (FEV
3. Persistent pneumococcal colonisation in antiretroviral-treated HIV infection is associated with nasal inflammation.
ART-treated PLWH exhibit persistent epithelial-driven neutrophilic nasal inflammation with neutrophil senescence and T-cell exhaustion. This immune landscape correlates with higher pneumococcal carriage density, suggesting that targeting epithelial-immune crosstalk or neutrophil senescence could reduce pathogen burden.
Impact: Defines tissue-specific immune dysfunction under ART with mechanistic links to bacterial colonization, informing precision prevention strategies for respiratory infections in PLWH.
Clinical Implications: Beyond vaccination, interventions modulating epithelial chemokine signaling or reversing neutrophil senescence may complement strategies to reduce pneumococcal carriage and disease in PLWH on ART.
Key Findings
- Long-term ART does not restore nasal mucosal immunity: persistent epithelial-driven neutrophilic inflammation, T-cell exhaustion, and cellular senescence.
- Neutrophils show mitochondrial stress, SASP gene expression, and impaired oxidative burst, especially in pneumococcal carriers.
- Neutrophilic inflammation correlates strongly with pneumococcal carriage density, implying a feedforward loop sustaining colonization.
Methodological Strengths
- Multi-omic profiling combining flow cytometry, single-cell transcriptomics, and functional assays in primary human samples
- Direct linkage of immune phenotypes to quantitative colonization density
Limitations
- Observational design limits causal inference; sample size and ART regimen heterogeneity not detailed in abstract
- Generalizability may vary across geographies and microbiome contexts
Future Directions: Interventional studies targeting epithelial chemokines or neutrophil senescence pathways; longitudinal cohorts to test whether immune modulation reduces carriage and invasive disease.
Despite systemic viral suppression, people living with HIV (PLHIV) on antiretroviral therapy (ART) remain highly susceptible to pneumococcal colonisation and disease. Here, we show that long-term ART does not restore nasal mucosal immunity. Using flow cytometry, single-cell transcriptomics, and neutrophil functional assays, we identify a persistent mucosal immune signature in PLHIV-ART > 1 yr marked by epithelial-driven neutrophilic inflammation, T cell exhaustion, and cellular senescence. Neutrophils exhibit mitochondrial stress, senescence-associated secretory phenotype (SASP) gene expression, and impaired oxidative burst, particularly in individuals with pneumococcal carriage. Epithelial cells express elevated neutrophil-recruiting ligand genes, while nasal T cells display pro-apoptotic and exhaustion gene profiles. Neutrophilic inflammation is strongly associated with pneumococcal carriage density, implicating a feedforward loop between inflammation and microbial persistence. Our findings reveal tissue-specific immune dysregulation despite ART and suggest that targeting epithelial-immune signalling or neutrophil senescence may offer novel therapeutic avenues to reduce respiratory pathogen burden in PLHIV.