Daily Respiratory Research Analysis
Analyzed 137 papers and selected 3 impactful papers.
Summary
Three high-impact respiratory studies span mechanism and translation: (1) a mechanistic Immunity study uncovers how influenza-infected CCR2+ pro-DC3 myeloid cells traffic to the heart, infect cardiomyocytes, and trigger IFN-I receptor signaling that drives myocardial injury; (2) a Nature Communications study shows that inhibiting DNA-PKcs (PRKDC) activates cGAS/STING via MYC degradation to enhance antitumor immunity and immunotherapy response in small-cell lung cancer; (3) another Nature Communications paper rationally designs EV-D68 VP1 capsid inhibitors with nanomolar potency and in vivo efficacy, including delayed-treatment benefit.
Research Themes
- Virus–host crosstalk and extra-pulmonary injury mechanisms
- DNA damage repair targeting to potentiate lung cancer immunotherapy
- Structure-guided antivirals against respiratory enteroviruses
Selected Articles
1. Influenza hijacks myeloid cells to inflict type-I interferon-fueled damage in the heart.
This mechanistic study shows that influenza-infected CCR2+ pro-DC3 myeloid cells home to the heart, where the virus spreads to cardiomyocytes and activates IFNAR1 signaling to drive tissue injury and functional impairment. Cardiomyocyte-specific dampening of IFNAR1 protects the heart without compromising pulmonary antiviral immunity.
Impact: It reveals a previously unrecognized lung–heart axis for influenza-mediated cardiac injury and identifies IFNAR1 signaling in cardiomyocytes as a targetable node.
Clinical Implications: Suggests that transient, cardiomyocyte-targeted modulation of IFN-I signaling could prevent cardiac complications of influenza while preserving antiviral defenses; informs risk stratification and therapeutic development.
Key Findings
- CCR2high circulating pro-DC3 myeloid cells become infected after pulmonary influenza and are chemoattracted to the CCL2-rich heart.
- Infected pro-DC3 release virus in the myocardium, leading to cardiomyocyte infection, IFN-I production, and IFNAR1-dependent tissue injury and dysfunction.
- Cardiomyocyte-specific genetic/therapeutic dampening of IFNAR1 protects cardiac tissue without impairing lung antiviral immunity.
Methodological Strengths
- Integrated human and murine evidence with mechanistic dissection across cell trafficking, infection, and signaling.
- Functional validation via cardiomyocyte-specific IFNAR1 modulation demonstrating organ-selective protection.
Limitations
- Preclinical nature limits immediate translation; optimal timing and safety of IFNAR1 modulation in humans remain unknown.
- Specificity to influenza strains and generalizability to other respiratory viruses require further study.
Future Directions: Evaluate cardiomyocyte-targeted IFNAR1/cGAS–STING pathway modulation in large animal models; identify biomarkers (e.g., CCR2+ pro-DC3 signatures) for early cardiac risk stratification in influenza.
Abundant evidence has correlated influenza infection with cardiovascular disease, yet mechanisms linking infection with the heart remain poorly understood. Here, we show that influenza infection damaged the human and murine heart. In mice, we showed that shortly after pulmonary infection, the virus infected a circulating myeloid pro-dendritic cell 3 (pro-DC3) that expressed high concentrations of the chemokine receptor CCR2. The heart, which produces abundant CCL2, preferentially attracted infected pro-DC3. In the myocardium, the virus escaped pro-DC3, infected cardiomyocytes, and triggered production of type-I interferon (IFN-I). Engagement of the IFN-I receptor (IFNAR1) on cardiomyocytes caused tissue damage and compromised heart function. Genetically and therapeutically dampening IFNAR1 exclusively in cardiomyocytes protected the heart while preserving anti-viral immunity in the lung. Our results identify a series of host-pathogen interactions that propagate tissue damage and uncover an axis for intervention to mitigate cardiovascular risk following viral infection.
2. Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.
Across 179,000+ tumors, SCLC exhibits the highest PRKDC (DNA-PKcs) expression, which predicts poor immunotherapy response. DNA-PKcs inhibition activates cGAS/STING via cytosolic dsDNA accumulation and triggers GSK3β-dependent proteasomal degradation of MYC, enhancing antitumor immunity and checkpoint blockade efficacy in SCLC models.
Impact: Identifies DNA-PKcs as a biomarker of immunotherapy resistance and as a druggable hub linking DNA repair, oncogene regulation, and innate sensing to reprogram the SCLC tumor-immune ecosystem.
Clinical Implications: Supports clinical evaluation of DNA-PKcs inhibitors to sensitize SCLC to immune checkpoint blockade and suggests PRKDC expression as a stratification biomarker.
Key Findings
- PRKDC (DNA-PKcs) is highest in SCLC among 24 tumor types and predicts poor immunotherapy response.
- DNA-PKcs depletion activates cGAS/STING via cytosolic dsDNA accumulation and enhances immunotherapy sensitivity in SCLC models.
- DNA-PKcs loss causes GSK3β-dependent proteasomal MYC degradation, linking NHEJ inhibition to oncogene downregulation.
Methodological Strengths
- Large-scale pan-cancer analysis combined with mechanistic validation in SCLC cell lines and mouse models.
- Convergent readouts (STING activation, MYC degradation, immunotherapy sensitization) support causal inferences.
Limitations
- Predominantly preclinical; efficacy and safety of DNA-PKcs inhibitors with checkpoint blockade in SCLC patients require trials.
- Potential tumor heterogeneity and resistance pathways beyond PRKDC were not fully explored clinically.
Future Directions: Prospective trials testing DNA-PKcs inhibitors plus PD-1/PD-L1 blockade in SCLC with biomarker-guided stratification (PRKDC/MYC/STING signatures); mapping resistance mechanisms to NHEJ targeting.
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays a high mutation burden; however, a modest response to immunotherapy. Improving Immunotherapy response in SCLC patients remains an unmet need. Here, we report that across 24 tumor types, including over 179,000 real-world patient tumors, SCLC has the highest expression of nonhomologous end joining (NHEJ) DNA repair regulator PRKDC (DNAPKcs). High PRKDC expression predicts poor response to immunotherapy in SCLC. DNAPKcs depletion causes activation of cGAS/STING pathway due to cytoplasmic accumulation of double-stranded DNA, inducing immunogenicity and enhancing sensitivity of SCLC models to immunotherapy. Analyses in SCLC cell lines and mouse models shows that depletion of DNAPKcs leads to proteasomal degradation of MYC via GSK3β pathway. We show that DNAPKcs upregulation contributes to immunotherapy resistance and DNAPKcs inhibition represents a promising therapeutic strategy to induce antitumor immunity and potentiate immunotherapy efficacy in immunologically suppressed SCLC.
3. Rational design and in vivo validation of capsid inhibitors for enterovirus D68.
Structure-guided VP1 capsid inhibitors (Jun11787, Jun11695) bind the hydrophobic canyon of EV-D68, exhibit nanomolar potency across strains, and show cross-activity against EV-A71 and CVB3. In neonatal mice, both compounds reduce spinal cord viral loads, prevent paralysis progression, and improve weight even with treatment delays up to 4–6 days.
Impact: Delivers first-in-class, broadly potent VP1 capsid inhibitors with in vivo proof-of-concept and delayed-treatment efficacy against a respiratory enterovirus lacking approved therapies.
Clinical Implications: Supports clinical development of VP1-targeted capsid inhibitors for EV-D68 outbreaks and AFM prevention; delayed-treatment benefit broadens real-world applicability.
Key Findings
- Cryo-EM revealed Jun11787 and Jun11695 binding within the VP1 hydrophobic canyon of EV-D68.
- Compounds showed nanomolar potency across multiple EV-D68 strains and micromolar activity against EV-A71 and CVB3 in vitro.
- In neonatal mouse models, treatment reduced spinal cord viral titers, prevented paralysis progression, and improved weight, effective even when started 4–6 days post-infection.
Methodological Strengths
- Structure-based drug design with cryo-EM validation of binding sites.
- Robust in vivo efficacy across immediate and delayed treatment windows using clinically relevant endpoints.
Limitations
- Preclinical neonatal mouse model may not fully recapitulate human disease and pharmacokinetics.
- Resistance emergence and safety profiles require comprehensive clinical evaluation.
Future Directions: Advance to phase I studies, define human pharmacokinetics/pharmacodynamics, assess resistance barriers, and explore combination strategies and pediatric formulations.
Enterovirus D68 (EV-D68) is a respiratory virus that causes neurological complications such as acute flaccid myelitis (AFM) and death in children. No vaccine or antiviral is available for EV-D68. We report the structure-based design of the EV-D68 VP1 capsid inhibitors with in vivo antiviral efficacy in a neonatal mouse model of EV-D68-associated paralytic myelitis. Cryo-EM structures show that Jun11787 and Jun11695 bind the hydrophobic canyon region in VP1 and display nanomolar potency against multiple EV-D68 strains and single-digit micromolar potency against EV-A71 and CVB3 in vitro. Jun11787 and Jun11695 also significantly reduce the spinal cord viral titer, prevent the progression of paralysis, and improve weight gain in EV-D68-infected male and female mice when treatment is initiated immediately, 24 h, and even 4-6 days post-infection. Overall, Jun11787 and Jun11695 represent promising leads for treating EV-D68 infection.