Respiratory Research Analysis
December’s respiratory research coalesced around five themes: host-directed antivirals, immune endotype switching in airway disease, epithelial–immune crosstalk in lung repair, multimodal AI diagnostics, and pediatric structural virology. A conserved HGS–coronavirus M interface emerged as a druggable host target with in vivo activity, while IL-17C–IL-17RE signaling was identified as a driver of neutrophilic endotype switching in bronchiectasis–asthma overlap. Dysplastic epithelial repair program
Summary
December’s respiratory research coalesced around five themes: host-directed antivirals, immune endotype switching in airway disease, epithelial–immune crosstalk in lung repair, multimodal AI diagnostics, and pediatric structural virology. A conserved HGS–coronavirus M interface emerged as a druggable host target with in vivo activity, while IL-17C–IL-17RE signaling was identified as a driver of neutrophilic endotype switching in bronchiectasis–asthma overlap. Dysplastic epithelial repair programs that trap tissue-resident lymphocytes were shown to impede alveolar regeneration after viral injury. Clinically, integrating a host biomarker (FABP4) with an LLM markedly improved ICU LRTI diagnosis, and cryo-EM resolved pediatric hMPV fusion epitopes to guide vaccines and antibodies.
Selected Articles
1. Structural basis for childhood antibody recognition of the human metapneumovirus fusion protein.
Five neutralizing pediatric mAbs mapped to four distinct epitopes on prefusion hMPV F, including a novel intratrimer interface site; cryo-EM and mouse prophylaxis confirm functional relevance and nominate pediatric-focused antigenic targets.
Impact: Provides rare, child-specific structural epitope maps with in vivo protection data, directly informing vaccine and monoclonal antibody design against hMPV.
Clinical Implications: Enables rational design of pediatric vaccines and prophylactic antibodies by prioritizing dominant epitopes validated structurally and functionally.
Key Findings
- Five neutralizing mAbs from children target four distinct epitopes on prefusion hMPV F.
- Cryo-EM resolved a fully intratrimer interface epitope on the F trimer.
- All mAbs showed prophylactic efficacy in mouse challenge models.
2. Evidence for Interleukin-17C governing interleukin-17A pathogenicity and promoting asthma endotype switching in bronchiectasis.
Human–mouse integrative data show IL-17C drives IL-17A via IL-17RE on ILC3s under chronic infection/allergen exposure, causing neutrophilic asthma endotype switching; Il17re ablation attenuates this pathway.
Impact: Positions IL-17C–IL-17RE signaling as a tractable target for difficult neutrophilic airway phenotypes in bronchiectasis–asthma overlap.
Clinical Implications: Motivates development of IL-17C/IL-17RE inhibitors and suggests IL-17C as a biomarker for endotype stratification.
Key Findings
- Peripheral IL-17C correlates with IL-17A and ILC3 levels in patients.
- In vivo, IL-17C via IL-17RE on ILC3s drives neutrophilic endotype switching.
- Il17re ablation reduces ILC3 responses and IL-17A-mediated switching.
3. Dysplastic epithelial repair promotes the tissue residence of lymphocytes to inhibit alveolar regeneration post viral infection.
Dysplastic KRT5+ epithelial repair after severe viral injury promotes tissue-resident lymphocyte accumulation that inhibits alveolar regeneration, revealing a repair–immune feedback loop that constrains recovery.
Impact: Defines a targetable epithelial–immune crosstalk limiting lung regeneration, informing regenerative and immunomodulatory strategies.
Clinical Implications: Supports interventions that reprogram repair pathways or modulate tissue-resident lymphocyte maintenance to restore alveolar regeneration after severe pneumonia.
Key Findings
- Dysplastic KRT5+ repair arises after severe viral infection.
- This repair state promotes tissue residence of lymphocytes in injured lung.
- Tissue-resident lymphocytes inhibit alveolar regeneration.
4. Targeting the host factor HGS-viral membrane protein interaction in coronavirus infection.
Genome-wide CRISPRi identified HGS as a conserved host factor binding coronavirus M to enable ERGIC trafficking and virion assembly; M-derived peptides and riboflavin tetrabutyrate disrupted this interface, blocking assembly with pan-coronavirus activity in vitro and in vivo.
Impact: Opens a host-directed antiviral path less prone to resistance by targeting a conserved host–virus interface with an immediately repurposable compound.
Clinical Implications: Supports translational progression of HGS inhibitors (peptides or RTB) pending ADME/toxicology, with potential broad-spectrum use for future coronavirus outbreaks.
Key Findings
- CRISPRi implicates HGS as essential for pan-coronavirus infection and virion assembly.
- HGS–M interaction enables ERGIC trafficking; its disruption retains M in ER and blocks assembly.
- Repurposed RTB and M-derived peptides disrupt HGS–M, showing in vivo efficacy.
5. Integrating a host biomarker with a large language model for diagnosis of lower respiratory tract infection.
In critically ill adults, combining the pulmonary transcriptomic biomarker FABP4 with GPT-4 EMR analysis yielded a multimodal classifier (AUC ≈0.93; 96% accuracy in independent validation) that outperformed biomarker-only, LLM-only, and clinician admission diagnoses.
Impact: Demonstrates a deployable paradigm where LLMs plus host biomarkers produce large diagnostic gains for ICU LRTI.
Clinical Implications: Could enable faster, more accurate antimicrobial decisions and targeted testing; multicenter prospective studies should precede deployment.
Key Findings
- FABP4 + GPT-4 classifier achieved AUC 0.93 and 84% accuracy; validation cohort reached AUC 0.98 and 96% accuracy.
- Outperformed FABP4-only, LLM-only, and admission clinician diagnoses.
- Independent validation supports reproducibility and generalizability.