Respiratory Research Analysis
Respiratory science in 2025 was defined by host-directed mechanisms, platform-ready biologics, and organelle-to-tissue–level mechanistic clarity. A protein language model generated de novo paired heavy/light-chain antibodies across multiple respiratory pathogens, inaugurating a rapid-response biologics paradigm. Two convergent lines of work reshaped antiviral strategy: discovery of MFSD6 as the bona fide EV-D68 receptor enabling decoy and receptor-blocking approaches, and a CRISPRa-guided identi
Summary
Respiratory science in 2025 was defined by host-directed mechanisms, platform-ready biologics, and organelle-to-tissue–level mechanistic clarity. A protein language model generated de novo paired heavy/light-chain antibodies across multiple respiratory pathogens, inaugurating a rapid-response biologics paradigm. Two convergent lines of work reshaped antiviral strategy: discovery of MFSD6 as the bona fide EV-D68 receptor enabling decoy and receptor-blocking approaches, and a CRISPRa-guided identification of P-selectin as a modifiable vascular adhesion axis with in vivo viral clearability. Foundational structural biology mapped the in-cell architecture of the mitochondrial respiratory chain and, together with an oxygen–mitochondrial citrate export axis, repositioned organelle metabolism as a driver of airway fate. An evolution-aware pipeline preemptively redesigned a clinical antibody to retain breadth, while RNA-level evolution via variant TRS/sgRNAs reframed interferon evasion and surveillance. Manufacturing quality emerged as biology: minimizing defective interfering particles expanded LAIV mucosal breadth. Early-life immunity was mechanistically linked to asthma risk via maternal allergy and neonatal RSV through FcRn/FcγR-mediated priming, sharpening prevention windows.
Selected Articles
1. Generation of antigen-specific paired-chain antibodies using large language models.
A protein language model generated de novo, human paired heavy/light-chain antibodies that bind antigens from SARS-CoV-2, H5N1, and RSV-A, demonstrating a template-free, cross-pathogen discovery platform for rapid biologics.
Impact: Establishes a generalizable, rapid-response route to antibody discovery that can compress timelines for countermeasures against emerging respiratory threats.
Clinical Implications: If in vivo neutralization, developability, and safety are validated, this approach could accelerate therapeutic and prophylactic antibody pipelines and improve outbreak readiness.
Key Findings
- Language model generated paired VH/VL antibodies de novo from sequence alone.
- Binding validated across SARS-CoV-2, H5N1, and RSV-A.
- Produced novel and diverse sequences without structural templates.
Methodological Strengths
- Template-free generative modeling of paired antibody chains with experimental binding validation.
- Cross-pathogen demonstration spanning multiple high-priority respiratory threats.
Limitations
- In vivo efficacy, developability, and safety were not yet established.
- Potential biases from training data may influence sequence space exploration.
Future Directions: Validate neutralization breadth and pharmacology in vivo, integrate liability prediction and manufacturability filters, and operationalize rapid-response design-to-test pipelines.
Abstract not available from provided dataset; see summary.
2. MFSD6 is an entry receptor for enterovirus D68.
MFSD6 was established as the cellular entry receptor for EV-D68, providing a mechanistic basis for host tropism and enabling receptor-blocking and decoy strategies to prevent infection and severe outcomes including AFM.
Impact: Orthogonal receptor validation consolidates a tractable, host-directed intervention point against a pediatric-relevant respiratory neurotropic pathogen.
Clinical Implications: Enables development of receptor-blocking antibodies/small molecules and engineered decoys; supports tissue expression–based risk stratification.
Key Findings
- MFSD6 is the bona fide entry receptor for EV-D68.
- Mechanistic basis for host cell attachment and tropism.
- Clear path to receptor-targeted therapies and decoys.
Methodological Strengths
- Orthogonal validation across genetic, biochemical, and cell-entry assays.
- Mechanistic mapping of receptor domains mediating viral recognition.
Limitations
- Human in vivo efficacy and safety of receptor-targeted interventions remain to be tested.
- Potential clade-specific differences require cross-lineage validation.
Future Directions: Advance MFSD6 decoys and blockers into pediatric-focused preclinical and early clinical studies; integrate receptor expression maps into surveillance and AFM risk modeling.
Abstract not available from provided dataset; see summary.
3. In-cell architecture of the mitochondrial respiratory chain.
Using in-cell cryo-electron tomography, the study visualized native respiratory complexes and supercomplex assemblies in intact cells, linking spatial organization to electron transfer and proton pumping efficiency in vivo.
Impact: Delivers native-context structural biology that underpins bioenergetics and respiratory pathophysiology, enabling organelle-aware biomarkers and interventions.
Clinical Implications: Supports hypotheses for mitochondrial biomarkers and therapies that modulate supercomplex organization in respiratory diseases.
Key Findings
- In situ visualization of respiratory complexes and supercomplexes in intact cells.
- Structural basis connecting organization to electron transfer and proton pumping.
- Foundation for linking mitochondrial architecture to disease phenotypes.
Methodological Strengths
- State-of-the-art in-cell cryo-ET revealing native macromolecular organization.
- Correlation of structural organization with functional bioenergetic readouts.
Limitations
- Primarily structural and hypothesis-generating without direct clinical outcomes.
- Generalizability across cell types and disease states requires further study.
Future Directions: Map disease- and hypoxia-induced remodeling of supercomplexes, develop drugs that modulate complex assembly, and validate organelle-level biomarkers in patient cohorts.
Abstract not available from provided dataset; see summary.
4. Live attenuated influenza vaccine with low proportions of defective interfering particles elicits robust immunogenicity and cross-protection.
Mouse studies showed that low-DIP LAIV induces stronger mucosal/systemic immunity and complete cross-protection against lethal H3N2/H1N1 challenges compared with high-DIP LAIV, elevating manufacturing control as an immunogenic determinant.
Impact: Links process engineering to immunogenic breadth, providing a generalizable lever for improving mucosal vaccines and preparedness.
Clinical Implications: Human validation of DIP minimization could enhance LAIV effectiveness and inform quality attributes for lot release in next-generation mucosal vaccines.
Key Findings
- Low-DIP LAIV elicited stronger mucosal and systemic immunity than high-DIP LAIV.
- Complete cross-protection against multiple lethal influenza challenges.
- Enhanced antigen presentation and mucosal cellular responses under low DIP.
Methodological Strengths
- Controlled manipulation and quantification of DIPs across vaccine lots.
- Robust challenge models with multi-strain, lethal endpoints.
Limitations
- Preclinical (murine) findings require human confirmation.
- Manufacturing scalability and standardized DIP assays need establishment.
Future Directions: Develop validated DIP assays for human lots, test low-DIP LAIV in phase 2/3 trials, and generalize DIP control principles to other mucosal vaccine platforms.
Abstract not available from provided dataset; see summary.
5. The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export.
Ambient oxygen directs airway epithelial differentiation by regulating mitochondrial citrate export, positioning citrate export as a metabolic control point linking oxygen tension to epithelial fate decisions.
Impact: Defines an oxygen–metabolism–differentiation axis that bridges organelle bioenergetics with airway biology and regenerative strategies.
Clinical Implications: Motivates optimization of oxygen tension and citrate/acetyl-CoA metabolism in airway organoids, and exploration of citrate-export modulation to tune epithelial composition.
Key Findings
- Ambient oxygen levels steer airway epithelial differentiation.
- Mitochondrial citrate export links oxygen to fate decisions.
- Repositions oxygen as a metabolic/developmental cue in airway biology.
Methodological Strengths
- Mechanistic dissection with metabolic flux manipulation and organoid models.
- Convergent evidence across oxygen tension, mitochondrial transport, and fate mapping.
Limitations
- Translational biomarker-readouts need validation in human airway tissues in vivo.
- Potential context specificity across airway regions and disease states.
Future Directions: Engineer metabolic microenvironments in airway models, identify druggable nodes in citrate export, and test organelle-aware therapies for chronic airway disease.
Abstract not available from provided dataset; see summary.
6. Maternal allergy and neonatal RSV infection synergize via FcR-mediated allergen uptake to promote the development of asthma in early life.
Registry-linked analyses and neonatal models show that maternal allergen sensitization combined with neonatal RSV-like infection amplifies FcRn/FcγR-mediated allergen uptake, drives cDC2 maturation and Th2 programming, and increases subsequent asthma risk.
Impact: Mechanistically connects perinatal immune programming to childhood asthma and identifies modifiable timing and targets for prevention.
Clinical Implications: Supports risk stratification and maternal/infant-targeted interventions to interrupt FcRn/FcγR-mediated priming around RSV exposure.
Key Findings
- Higher later asthma risk among infants with RSV bronchiolitis born to allergic/asthmatic parents.
- Neonatal viral infection upregulates Fc receptors and matures cDC2, priming Th2 responses.
- Maternal allergen-specific IgG via FcRn enhances FcγR-mediated allergen uptake and Th2 programming.
Methodological Strengths
- Registry-linked human data integrated with mechanistic neonatal models.
- Causal pathway dissection implicating FcRn/FcγR and dendritic cell programming.
Limitations
- Translational interventions targeting Fc pathways in humans remain to be tested prospectively.
- Population heterogeneity and environmental co-exposures may modulate effect sizes.
Future Directions: Design maternal/infant trials timing RSV season to interrupt Fc-mediated priming; identify biomarkers for early-life risk stratification and targeted prevention.
Abstract not available from provided dataset; see summary.
7. A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases.
UNAGI models time-series single-cell transcriptomic dynamics to prioritize drug candidates; in pulmonary fibrosis, it predicted repurposable agents and validated nifedipine’s anti-fibrotic effects in human precision-cut lung slices with proteomic support.
Impact: Bridges single-cell disease trajectories with actionable drug prioritization and ex vivo validation, accelerating therapeutic discovery in respiratory fibrosis.
Clinical Implications: Offers a preclinical prioritization platform for repurposing and early-phase trials in pulmonary fibrosis; informs candidate and biomarker selection.
Key Findings
- Captured time-resolved single-cell disease trajectories and improved drug perturbation modeling.
- Predicted antifibrotic candidates; nifedipine validated ex vivo in human lung tissue.
- Proteomic data corroborated inferred dynamics; framework generalized to other diseases.
Methodological Strengths
- Integrative generative modeling with external ex vivo validation in human tissue.
- Mechanistically interpretable trajectories supporting drug mechanism hypotheses.
Limitations
- Prospective, multi-center clinical validation is needed to confirm translational impact.
- Model performance may vary with dataset quality and sampling frequency.
Future Directions: Prospective deployment with biomarker-linked early-phase trials; expand to other respiratory diseases and integrate multi-omic measurements.
Abstract not available from provided dataset; see summary.
8. P selectin promotes SARS-CoV-2 interactions with platelets and the endothelium.
A CRISPRa screen identified P-selectin as a host factor that enhances spike-dependent binding and vascular homing/platelet aggregation; blocking P-selectin interactions cleared vascular-associated pulmonary virus in vivo.
Impact: Reveals a modifiable vascular adhesion axis with in vivo support, enabling host-directed antiviral adjuncts for severe coronavirus disease.
Clinical Implications: Supports development of P-selectin–targeted strategies to mitigate vascular sequestration and thromboinflammation in respiratory viral disease.
Key Findings
- P-selectin emerged from CRISPRa as a validated suppressor of SARS-CoV-2 infection.
- P-selectin increases spike-dependent binding and mediates vascular homing and platelet aggregation.
- Blocking P-selectin interactions cleared pulmonary vascular virus in vivo.
Methodological Strengths
- Genome-scale CRISPRa screening coupled with mechanistic validation.
- In vivo functional blockade demonstrating therapeutic clearability.
Limitations
- Virus–host interactions and clearance dynamics may vary across variants and species.
- Clinical translation requires evaluation of safety, timing, and patient selection.
Future Directions: Test P-selectin inhibitors or blocking biologics in respiratory viral models and early-phase trials; integrate vascular biomarkers into risk stratification.
Abstract not available from provided dataset; see summary.
9. Preemptive optimization of a clinical antibody for broad neutralization of SARS-CoV-2 variants and robustness against viral escape.
An integrated pipeline of deep mutational scanning, structure-guided design, and machine learning redesigned a clinical antibody to restore and broaden neutralization across current and prospective escape variants while avoiding new vulnerabilities.
Impact: Provides a reusable, evolution-aware blueprint to future-proof monoclonal antibodies against rapidly evolving respiratory viruses.
Clinical Implications: Supports periodic computational updates of clinical antibodies to preserve prophylactic and therapeutic options, especially for immunocompromised patients.
Key Findings
- DMS mapped vulnerability hotspots in the parental antibody.
- Redesign improved potency and breadth across diverse variants.
- No new susceptibility hotspots emerged in redesigned antibody by DMS.
Methodological Strengths
- Closed-loop design integrating DMS constraints, structural modeling, and ML.
- Prospective evaluation across current and hypothetical escape variants.
Limitations
- Clinical efficacy against real-world variant waves remains to be confirmed.
- Manufacturability and immunogenicity of redesigned antibodies require assessment.
Future Directions: Institutionalize periodic antibody redesign cycles tied to surveillance; extend to other respiratory pathogens and polyclonal modalities.
Abstract not available from provided dataset; see summary.
10. Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.
Global analyses and functional experiments reveal convergently evolved TRSs that generate novel sgRNAs, including a truncated N sgRNA antagonizing type I interferon and increasing viral fitness, highlighting RNA-level evolution beyond amino acid changes.
Impact: Exposes an RNA-level evolutionary mechanism shaping interferon evasion and fitness, advocating TRS/sgRNA-aware surveillance and therapeutics.
Clinical Implications: Supports integrating TRS/sgRNA features into variant risk assessment and exploring antivirals targeting TRS-dependent transcription or sgRNA functions.
Key Findings
- Convergent emergence of novel TRSs upstream of structural genes.
- Truncated N sgRNA antagonizes type I interferon and confers fitness advantages.
- Demonstrates functional RNA-level evolution beyond protein coding changes.
Methodological Strengths
- Integration of global genomic surveillance with mechanistic validation.
- Dissection of sgRNA functions and interferon antagonism in vitro and in models.
Limitations
- Clinical correlates of TRS/sgRNA features require prospective validation.
- Scope centered on SARS-CoV-2; generalization to other RNA viruses needs study.
Future Directions: Embed TRS/sgRNA metrics into variant triage and explore inhibitors of transcriptional regulatory switches or pathogenic sgRNAs.
Abstract not available from provided dataset; see summary.