Daily Respiratory Research Analysis
Three impactful studies span mechanistic immunology, biomarker-driven prognosis, and infection control. Interstitial macrophages were shown to restrain SARS-CoV-2 via type I interferon signaling in a rigorous preclinical study. In clinical domains, soluble Galectin-9 and TIM-3 stratified cancer mortality risk in obstructive sleep apnea, and a time-series analysis showed hospital masking alone was insufficient to sustain near-zero health care–associated respiratory viral infections post-pandemic.
Summary
Three impactful studies span mechanistic immunology, biomarker-driven prognosis, and infection control. Interstitial macrophages were shown to restrain SARS-CoV-2 via type I interferon signaling in a rigorous preclinical study. In clinical domains, soluble Galectin-9 and TIM-3 stratified cancer mortality risk in obstructive sleep apnea, and a time-series analysis showed hospital masking alone was insufficient to sustain near-zero health care–associated respiratory viral infections post-pandemic.
Research Themes
- Tissue-resident macrophage regulation of respiratory viral pathogenesis
- Immune checkpoint biomarkers linking sleep apnea hypoxemia to cancer outcomes
- Hospital infection control policies and health care–associated respiratory viral infections
Selected Articles
1. Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling.
In a mouse model of SARS-CoV-2, depletion of nerve- and airway-associated interstitial macrophages caused uncontrolled viral spread, hyperinflammation, and 100% mortality. NAM-intrinsic type I interferon receptor signaling was essential to limit inflammation and viral dissemination, highlighting NAMs as key tissue-resident regulators of coronavirus pathogenesis.
Impact: This study uncovers a cell-type–specific interferon mechanism by tissue-resident macrophages that restrains SARS-CoV-2 pathogenesis, offering a precise target for host-directed therapy. It advances fundamental understanding of local immune regulation in viral pneumonia.
Clinical Implications: Therapeutic strategies that preserve or augment NAM IFNAR signaling may mitigate severe COVID-19 by limiting lung viral dissemination and hyperinflammation. Conversely, interventions that broadly suppress type I IFN signaling in the lung could be harmful.
Key Findings
- NAM depletion in mice led to enhanced lung viral spread, heightened inflammation, and 100% mortality after MA-10 infection.
- Control mice restricted viral distribution and survived, indicating a protective role of NAMs.
- NAM-intrinsic type I interferon receptor (IFNAR) signaling was critical for limiting inflammation and viral dissemination.
Methodological Strengths
- Use of a mouse-adapted SARS-CoV-2 strain with targeted depletion of NAMs to assess causal roles.
- Cell-type–specific interrogation of IFNAR signaling to define mechanisms limiting inflammation and viral spread.
Limitations
- Findings are from mouse models using a mouse-adapted strain and may not fully translate to humans.
- Human validation and therapeutic modulation of NAMs/IFNAR signaling were not tested.
Future Directions: Validate NAM phenotypes and IFNAR signaling in human lung tissues during COVID-19 and test strategies to selectively boost NAM antiviral programs without exacerbating inflammation.
Despite vaccines, rapidly mutating viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to threaten human health due to an impaired immunoregulatory pathway and a hyperactive immune response. Our understanding of the local immune mechanisms used by tissue-resident macrophages to safeguard the host from excessive inflammation during SARS-CoV-2 infection remains limited. Here, we found that nerve- and airway-associated interstitial macrophages (NAMs) are required to control mouse-adapted SARS-CoV-2 (MA-10) infection. Control mice restricted lung viral distribution and survived infection, whereas NAM depletion enhanced viral spread and inflammation and led to 100% mortality. Mechanistically, type I interferon receptor (IFNAR) signaling by NAMs was critical for limiting inflammation and viral spread, and IFNAR deficiency in CD169
2. Immune Checkpoint Biomarkers Galectin-9 and TIM-3 Predict Melanoma and Lung Cancer Mortality in Obstructive Sleep Apnoea.
Across three cohorts (n=684), higher plasma sGalectin-9 and sTIM-3 identified severe OSA patients with melanoma or lung cancer at increased mortality risk. In vitro and ex vivo data indicated intermittent hypoxia upregulates these checkpoints, correlating with inflammation and reduced T-cell proliferation/infiltration, linking OSA hypoxemia to tumor immune evasion.
Impact: Introduces immune checkpoint biomarkers for prognostic stratification in OSA-related cancer, supported by mechanistic data linking hypoxemia to immune suppression.
Clinical Implications: sGalectin-9 and sTIM-3 could guide risk stratification and prioritization of aggressive OSA management and cancer surveillance. They may also inform selection for immunomodulatory strategies, pending validation.
Key Findings
- In severe OSA with melanoma or lung cancer, higher sGalectin-9 and sTIM-3 associated with tumor aggressiveness and increased mortality risk.
- Biomarker levels were higher in severe OSA across three cohorts; monocyte intracellular Galectin-9 and T-cell membrane TIM-3 were upregulated.
- Intermittent hypoxia induced biomarker expression, positively correlated with inflammatory mediators and inversely with T-cell proliferation/infiltration.
Methodological Strengths
- Prospective multicohort design with consistent biomarker assessments across cohorts.
- Mechanistic support via in vitro and ex vivo models linking intermittent hypoxia to biomarker upregulation and immune effects.
Limitations
- Observational design limits causal inference and generalizability to all OSA populations.
- Optimal clinical cut-offs and integration with existing prognostic models were not established.
Future Directions: Validate prognostic thresholds in larger, diverse cohorts; test whether biomarker-guided OSA treatment intensity or cancer therapies improve outcomes.
OBJECTIVES: Obstructive sleep apnoea (OSA) has been associated with increased cancer risk and mortality, yet specific biomarkers for patient stratification remain lacking. This study explores the role of immune checkpoint biomarkers, soluble Galectin-9 (sGalectin-9) and TIM-3 (sTIM-3), in identifying OSA patients at higher risk of cancer-related mortality. METHODS: We conducted a multicohort, prospective observational study including 684 patients, with and without cancer, who underwent sleep studies. Plasma levels of sGalectin-9 and sTIM-3 were assessed using bead-based multiplexed assays. In vitro and ex vivo models were employed to investigate the pathogenic mechanisms underlying biomarker upregulation and their immunological impact. RESULTS: In severe OSA patients with melanoma or lung cancer, sGalectin-9 and sTIM-3 were associated with tumour aggressiveness and with an increased mortality risk. In the three study cohorts, biomarker levels were higher in severe OSA patients than in the other groups. In non-cancer OSA patients' monocyte intracellular Galectin-9 and T-lymphocyte membrane-bound TIM-3 were upregulated. Experimental data revealed that intermittent hypoxia drove the expression of these biomarkers, which were positively associated with inflammatory mediators and inversely related to T-cell proliferation and infiltration. These findings underscore a mechanistic link between hypoxemia and immune suppression. INTERPRETATION: sGalectin-9 and sTIM-3 are promising prognostic biomarkers for medium- to long-term survival in OSA patients with melanoma or lung cancer. Their upregulation highlights a potential pathophysiological pathway connecting OSA-induced hypoxemia to cancer aggressiveness through immune modulation. Further validation could inform risk stratification and personalised therapeutic strategies.
3. Trends in health care-associated non-SARS-CoV-2 respiratory viral infections in conjunction with masking policies during and after the COVID-19 pandemic: A time-series analysis.
Across two hospitals (2016–2024), HA-RVI dropped to near-zero during universal masking plus other measures, but rebounded postpandemic when other measures were withdrawn, despite continued masking. Interrupted time-series showed an immediate decrease with combined measures and an immediate, sustained increase after stand-down, indicating masking alone was insufficient.
Impact: Provides long-horizon, policy-relevant evidence that hospital masking, without accompanying measures, does not sustain near-zero HA-RVI rates postpandemic.
Clinical Implications: Hospitals should consider layered infection-prevention strategies (e.g., symptom screening, ventilation, cohorting, testing) rather than relying on masking alone to control non–SARS-CoV-2 respiratory viruses.
Key Findings
- HA-RVI rates fell to near-zero during universal masking combined with other mitigation measures.
- Postpandemic, with other measures stood down but masking continued, HA-RVI rebounded with an immediate and increasing trend.
- Interrupted time-series confirmed immediate level changes at both the introduction and withdrawal of broader measures.
Methodological Strengths
- Longitudinal dataset spanning pre-, during-, and postpandemic periods across two hospitals.
- Use of interrupted time-series analysis to assess immediate and trend effects of policy changes.
Limitations
- Ecological design with potential confounding from unmeasured concurrent changes.
- Lack of pathogen-specific breakdown and limited generalizability beyond the two hospitals.
Future Directions: Quantify contributions of specific interventions (ventilation, testing, cohorting) and evaluate optimized, layered bundles to sustainably reduce HA-RVI.
BACKGROUND: While introduction of universal masking was associated with significant declines in health care-associated-respiratory-viral-infections (HA-RVI), subsequent studies have shown mixed results. We sought to evaluate the impact on HA-RVI when masking was continued in the postpandemic period. METHODS: Observational study in 2 Singaporean hospitals from January 1, 2016 to April 30, 2024. Prepandemic, masking (surgical masks) was only practiced in high-risk wards. During the pandemic, masking was made mandatory hospital-wide, together with other extensive mitigation measures; in the postpandemic phase, other mitigation measures were stood-down but masking in hospitals was continued. Interrupted time-series analysis was utilized to compare trends in HA-RVI. RESULTS: During the pandemic, HA-RVI fell to near-zero. In the postpandemic phase, when other mitigation measures were stood-down but masking in hospitals was continued, HA-RVI rebounded. Time-series analysis showed immediate decrease in HA-RVI following imposition of universal masking, together with other mitigation measures during the pandemic; postpandemic, there was both an immediate increase in HA-RVI, as well as a significant increase in the trend of HA-RVI over time, despite continuation of masking. CONCLUSIONS: HA-RVI rebounded in the postpandemic period after other mitigation measures were stood-down, even whilst masking continued in hospitals.