Daily Respiratory Research Analysis
Analyzed 202 papers and selected 3 impactful papers.
Summary
Analyzed 202 papers and selected 3 impactful articles.
Selected Articles
1. Conformational dynamics of SARS-CoV-2 spike on a membrane reveals the allosteric effects of furin cleavage and the D614G mutation.
Using HDX-MS on eVLP-displayed full-length spike, the authors show that membrane context enables sampling of conformations not accessible to soluble constructs. D614G stabilizes a closed prefusion interface that may reduce premature S1 shedding with a cleaved furin site, while furin cleavage allosterically increases S2' flexibility, potentially enhancing TMPRSS2 processing and infectivity.
Impact: This mechanistic work clarifies how sequence and proteolysis remodel spike energetics on membranes, informing vaccine antigen design and protease-targeted interventions.
Clinical Implications: Insights into D614G- and furin-driven conformational control can guide stabilization strategies for vaccine antigens and inform the anticipated impact of protease activity on transmissibility and pathogenesis.
Key Findings
- eVLP-displayed full-length spike samples membrane-context conformations, including the open-interface trimer seen in soluble constructs.
- D614G favors a closed-interface prefusion conformation, likely reducing premature S1 shedding in the presence of a cleaved furin site.
- Furin cleavage at S1/S2 allosterically increases S2' flexibility, potentially facilitating TMPRSS2 processing and enhancing infectivity.
- HDX-MS with eVLPs provides a general platform to interrogate viral membrane proteins in near-native environments.
Methodological Strengths
- Near-native membrane context via eVLPs displaying full-length spike enables physiologically relevant HDX-MS mapping.
- Direct comparison of sequence features (e.g., D614G) and proteolytic states (furin-cleaved) on conformational energetics.
Limitations
- No direct in vivo infectivity or transmission experiments; mechanistic inferences are indirect.
- Focuses on spike; generalization to other viral proteins or cell types was not evaluated.
Future Directions: Extend eVLP-HDX-MS to diverse variants and host protease milieus, and correlate conformational states with cell entry kinetics and transmissibility.
By combining hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS) with the ability of enveloped virus-like particles (eVLPs) to display full-length native-like severe acute respiratory syndrome coronavirus 2 spike protein, we have determined the energetic and conformational effects of both the membrane environment and unique sequence features that are considered incompatible with soluble protein constructs. We find that eVLP-displayed spike can sample the open-interface trimer conformation observed in soluble constructs of spike, including sequences from engineered vaccine constructs and native viral sequences inaccessible to studies on soluble constructs. Moreover, the D614G mutation, which arose early in the pandemic, favors the canonical "closed-interface" prefusion conformation, potentially mitigating premature S1 shedding in the presence of a cleaved furin site and providing an evolutionary advantage to the virus. Furin cleavage at the S1/S2 boundary allosterically increases the flexibility of the S2' site, which may facilitate increased TMPRSS2 processing, enhancing viral infectivity. The use of eVLPs in HDX-MS studies provides a powerful platform for studying viral and membrane proteins in near-native environments.
2. Long-term risk of death after tuberculosis diagnosis and treatment.
In a nationwide matched cohort from Brazil, individuals diagnosed with TB and those who completed TB treatment had significantly elevated 14-year natural-cause mortality compared with TB-free controls, with increased deaths across cancer, cardiovascular, endocrine, respiratory, and external causes. The findings demonstrate that excess mortality persists long after treatment completion.
Impact: This large, methodologically rigorous study quantifies prolonged, cause-specific excess mortality after TB, reframing TB as a chronic condition requiring long-term surveillance and secondary prevention.
Clinical Implications: Post-TB care should include long-term risk assessment and integrated management of cardiometabolic, oncologic, and respiratory comorbidities, with smoking cessation and vaccination, and pathways for prolonged follow-up beyond treatment completion.
Key Findings
- 14-year natural-cause mortality risk was higher after TB diagnosis (RR 2.16, 95% CI 1.96–2.37) versus matched TB-free controls.
- After TB treatment completion, natural-cause mortality remained elevated (RR 1.77, 95% CI 1.55–2.03).
- Cause-specific mortality increased for cancer, cardiovascular, endocrine, respiratory, and external causes in both diagnosed and treated cohorts.
Methodological Strengths
- Nationwide linked datasets with large matched cohorts and long follow-up (up to 14 years).
- Competing risk analyses for natural and cause-specific mortality enhance causal interpretability.
Limitations
- Observational design with potential residual confounding and misclassification of causes of death.
- Generalizability outside Brazil may be limited; treatment era and HIV status granularity may vary.
Future Directions: Validate findings in diverse settings; develop and test post-TB care bundles targeting cardiovascular, oncologic, and respiratory risks; build risk prediction tools to personalize long-term follow-up.
Tuberculosis (TB) remains a major societal burden, yet data on long-term mortality following TB diagnosis and treatment are limited. We conducted a nationwide Brazilian cohort study using linked data (2004-2018) to quantify long-term mortality (up to 14 years) following TB. We matched: (i) individuals diagnosed with TB or (ii) individuals who had completed TB treatment to TB-free individuals. We used competing risk methods to analyze natural causes (that is, defined as deaths excluding TB, HIV and external causes) and cause-specific mortality. In the diagnosed cohort (185,921 pairs), the risk of 14-year natural cause mortality was significantly higher (risk ratio (RR) = 2.16, 95% confidence interval = 1.96-2.37); RRs were significantly elevated for deaths due to cancer, cardiovascular, endocrine, respiratory and external causes. The treated cohort (111,871 pairs) presented elevated natural cause mortality risk (RR = 1.77,1.55-2.03), with similarly increased RRs across specific causes. We showed that TB survivors, even after treatment, faced a significantly elevated, prolonged risk of death from various causes up to 14 years later. This finding highlights the need for long-term monitoring to reduce the burden of TB.
3. Incidence of respiratory syncytial virus and influenza: A Danish nationwide cohort study.
In a nationwide adult cohort (2011/12–2022/23), 962,858 ARIs were identified, with RSV accounting for 1.1% and influenza for 6.5%. RSV incidence rose over time and in 2022/23 was particularly high in older adults and those with comorbidities, where it approached influenza incidence, underscoring substantial adult RSV burden.
Impact: Provides robust, population-level incidence estimates for adult RSV across age and risk strata, directly informing vaccine policy, prioritization, and clinical pathways.
Clinical Implications: Supports targeting adult RSV vaccination to older adults and those with cardiopulmonary/hematologic comorbidities; informs resource planning for ARI seasons and diagnostic testing strategies.
Key Findings
- Among 962,858 adult ARIs, 10,437 (1.1%) were attributed to RSV and 62,869 (6.5%) to influenza.
- Overall ARI incidence increased over time; RSV incidence rose (0.2–91.6 per 100,000 person-years), while influenza fluctuated (6.7–322.0).
- In 2022/23, RSV incidence was higher in females, older adults (198.7 in ≥60 y; 303.2 in ≥75 y), and in those with comorbidities (e.g., hematologic disease 868.6; COPD 679.5).
- In older and comorbid adults, RSV incidence approximated influenza, highlighting substantial adult RSV burden.
Methodological Strengths
- Nationwide cohort over 12 seasons with comprehensive adult population coverage.
- Stratified incidence estimates by age, sex, and comorbidity enabling targeted inferences.
Limitations
- Attribution depends on registered ARI and testing practices; under-ascertainment and misclassification are possible.
- Causality cannot be inferred; outcomes (e.g., hospitalization severity) were not the primary focus.
Future Directions: Link incidence to clinical outcomes (hospitalization, mortality), evaluate vaccine impact post-implementation, and refine risk models for prioritization.
Respiratory syncytial virus (RSV) is, like influenza, one of the most common causes of severe acute respiratory infections (ARIs) in adults; however, its incidence across different risk and age groups is unknown. We estimated the incidence of registered ARIs in Danish adults, focusing on RSV and contextualizing with influenza. We conducted a nationwide cohort study in Denmark, including all adults aged ≥18 y with a registered ARI, during the 2011/12 to 2022/23 seasons. We estimated the incidence (per 100,000 person-years) of ARI overall and ARI attributable to RSV or influenza, overall and stratified by sex, age, and comorbidity. We identified 962,858 ARIs, of which 10,437 (1.1%) were attributed to RSV and 62,869 (6.5%) to influenza. The ARI incidence increased over time (range: 1,272-2,144), including a rise in RSV incidence (range: 0.2-91.6), while influenza incidence fluctuated (range: 6.7-322.0). In the 2022/23 season, RSV incidence was higher among females, older adults (198.7 in ≥60-y-olds, and 303.2 in ≥75-y-olds), and those with comorbidities, especially hematologic disease (868.6) and chronic obstructive pulmonary disease (679.5). Although influenza incidence was generally higher than RSV, the incidences were comparable for older adults and those with comorbidities. In conclusion, RSV is an important cause of ARIs among adults, comparable to influenza, particularly in older adults and those with comorbidities. These findings underscore the substantial burden of RSV that is relevant for public health planning and clinical decision-making, particularly given the recent approval of three highly effective RSV vaccines.