Respiratory Research Analysis
Respiratory research in 2025-Q1 coalesced around host-centric interventions, evolution-aware biologics, and organelle-level mechanisms. Two independent studies identified MFSD6 as the entry receptor for EV-D68, with January work engineering a protective MFSD6-Fc decoy and March providing orthogonal validation, rapidly enabling receptor-blocking strategies. Methodologically, in-cell cryo-electron tomography resolved the native architecture of the mitochondrial respiratory chain, aligning with an
Summary
Respiratory research in 2025-Q1 coalesced around host-centric interventions, evolution-aware biologics, and organelle-level mechanisms. Two independent studies identified MFSD6 as the entry receptor for EV-D68, with January work engineering a protective MFSD6-Fc decoy and March providing orthogonal validation, rapidly enabling receptor-blocking strategies. Methodologically, in-cell cryo-electron tomography resolved the native architecture of the mitochondrial respiratory chain, aligning with an oxygen–metabolism axis that controls airway epithelial fate via mitochondrial citrate export. Preemptive DMS/AI-guided antibody redesign offered a reproducible pathway to maintain antiviral breadth, while RNA-level evolution via TRS/sgRNAs reframed interferon evasion and surveillance priorities. Large-animal human ACE2 pig models expanded translational testing capacity, and immune-centric disease reframing emerged across cystic fibrosis (perinatal innate-immune dysfunction), allergic airway disease (lung-resident memory B cells sustaining IgE), and MIS-C (an EBV–TGF-β axis).
Selected Articles
1. In-cell architecture of the mitochondrial respiratory chain.
Using in-cell cryo-electron tomography, the study visualized native structures and spatial organization of respiratory complexes and supercomplexes in intact cells, linking architecture to in vivo electron transfer and proton pumping efficiency.
Impact: Delivers native-context structural biology that underpins bioenergetics and disease models, establishing an organelle-centric framework relevant to respiratory pathophysiology.
Clinical Implications: Enables hypotheses for mitochondrial biomarkers and interventions that modulate supercomplex organization in respiratory diseases, informing future translational studies.
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.
2. MFSD6 is an entry receptor for respiratory enterovirus D68.
Identified MFSD6 as a functional EV-D68 entry receptor and engineered an MFSD6-Fc decoy that blocks viral uptake in vitro and prevents lethality in neonatal mice.
Impact: First tractable host entry factor for EV-D68 with an effective decoy biologic, immediately opening a translational path toward outbreak protection in infants.
Clinical Implications: Enables receptor-directed prophylaxis or early therapy concepts; prioritizes cross-clade validation and safety/PK to prepare for pediatric deployment during outbreaks.
Key Findings
- MFSD6 mediates EV-D68 attachment and replication.
- Virus recognition involves MFSD6’s second extracellular domain.
- MFSD6-Fc decoy blocks uptake in vitro and prevents neonatal mouse lethality.
3. MFSD6 is an entry receptor for enterovirus D68.
Established MFSD6 as the cellular entry receptor for EV-D68, providing a molecular basis for tropism and a target to block attachment and entry.
Impact: Orthogonal validation of a bona fide host receptor consolidates a tractable intervention point for EV-D68 and acute flaccid myelitis risk mitigation.
Clinical Implications: Enables receptor-blocking antibodies and decoys, informs tissue-expression-based risk stratification and refined disease models.
Key Findings
- MFSD6 identified and validated as EV-D68 entry receptor.
- Mechanistic basis for host cell entry and tropism.
- Clear path to receptor-targeted therapies and decoys.
4. Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease.
Human ACE2 transgenic pigs support productive SARS-CoV-2 replication in upper and lower airways and recapitulate clinical and immunopathological features of severe human COVID-19.
Impact: Provides a high-fidelity large-animal platform to evaluate vaccines, antivirals, and immunomodulators at scales and physiological relevance beyond rodent models.
Clinical Implications: Accelerates dosing, route, and safety optimization before human trials, improving readiness against SARS-CoV-2 and related respiratory threats.
Key Findings
- Sustained viral replication in nasal, tracheal, and lung tissues.
- Clinical signs and lung immunopathology mirror severe COVID-19.
- Enables translational studies not feasible in rodents.
5. Perinatal dysfunction of innate immunity in cystic fibrosis.
Across newborn CF pigs and preschool children, the study shows a conserved perinatal innate-immune defect with immature myeloid infiltration, reduced CD16, and impaired phagocytosis/ROS generation before infection.
Impact: Reframes CF pathogenesis to include congenital innate-immune dysfunction, opening an early window for immune-targeted interventions beyond CFTR modulation.
Clinical Implications: Motivates early-life immune assessment, trials to enhance myeloid maturation and phagocytic function, and preventive strategies before overt lung disease.
Key Findings
- Perinatal innate-immune defect conserved across species.
- Reduced CD16 correlates with impaired phagocytosis and ROS.
- Defect precedes lung disease and may persist despite CFTR modulation.
6. The oxygen level in air directs airway epithelial cell differentiation by controlling mitochondrial citrate export.
Ambient oxygen directs airway epithelial differentiation via regulation of mitochondrial citrate export, positioning citrate export as a metabolic control point linking oxygen to epithelial fate decisions.
Impact: Defines an oxygen–metabolism–differentiation axis with implications for regeneration, organoid modeling, and metabolic targeting in chronic airway disease.
Clinical Implications: Suggests optimizing oxygen tension and citrate/acetyl-CoA metabolism in airway organoids and exploring citrate-export pathway 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.
7. Preemptive optimization of a clinical antibody for broad neutralization of SARS-CoV-2 variants and robustness against viral escape.
Integrated deep mutational scanning, structure-guided design, and machine learning to redesign a clinical antibody with restored and broadened neutralization across current and prospective escape variants while avoiding new vulnerabilities.
Impact: Provides a scalable, reproducible blueprint for evolution-resilient 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 identified vulnerability hotspots in the parental antibody.
- Redesign improved potency and breadth across diverse variants.
- No new susceptibility hotspots emerged in redesigned antibody by DMS.
8. Lung-resident memory B cells maintain allergic IgE responses in the respiratory tract.
Allergen inhalation models and lineage-tracing indicate that IgE class switching occurs predominantly in the lung and that lung-resident memory B cells sustain local IgE production.
Impact: Reorients allergic airway pathophysiology toward tissue-resident B-cell circuits, suggesting local niche disruption and class-switch modulation as therapeutic strategies.
Clinical Implications: Points to tissue-targeted immunomodulation in asthma/rhinitis and prioritizes translational studies in human airway tissues.
Key Findings
- IgE class switching predominantly occurs within the lung.
- Lung-resident memory B cells sustain airway IgE.
- Local memory circuits maintain persistent allergic responses.
9. TGFβ links EBV to multisystem inflammatory syndrome in children.
Multicenter translational work maps an EBV–TGF-β signaling axis associated with MIS-C immune phenotypes, proposing biomarkers and therapeutic targets along this host pathway.
Impact: Reframes MIS-C pathogenesis through a druggable host signaling pathway linked to prior viral exposure, creating avenues for biomarker-guided immunomodulation.
Clinical Implications: Supports evaluation of EBV reactivation and TGF-β signatures in suspected MIS-C and motivates trials of TGF-β pathway modulation as adjunctive therapy.
Key Findings
- Identified an EBV–TGF-β axis associated with MIS-C phenotypes.
- Linked prior viral exposure to post-SARS-CoV-2 hyperinflammation.
- Proposed TGF-β–axis biomarkers and therapeutic targets.
10. Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.
Global analyses and experiments reveal convergently evolved TRSs that generate novel sgRNAs, including a truncated N sgRNA that antagonizes type I interferon and increases viral fitness.
Impact: Uncovers an RNA-level evolutionary mechanism shaping interferon evasion and fitness, advocating TRS/sgRNA-aware surveillance and therapeutic design.
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 amino acid changes.