Daily Respiratory Research Analysis
Analyzed 133 papers and selected 3 impactful papers.
Summary
Three impactful respiratory papers span translational virology and clinical practice. A structural–mechanistic study identifies a conserved pivot epitope on RSV F targeted by broadly neutralizing nanobodies with in vivo efficacy. Complementing this, a PNAS study dissects how SARS-CoV-2 and MERS-CoV nsp1 differentially engage the integrated stress response to shut down host translation. Clinically, a large multicenter RCT shows no advantage of routine prophylactic high‑flow nasal oxygen after cardiac surgery, guiding resource‑conserving practice.
Research Themes
- RSV antibody therapeutics and conserved fusion epitopes
- Viral control of host translation and integrated stress response
- Perioperative respiratory support effectiveness after cardiac surgery
Selected Articles
1. Broadly neutralizing nanobodies target a defined structural pivot site on the RSV fusion protein.
Two potent nanobodies (1G9, 1D8) neutralize RSV A/B by engaging a conserved pivot within antigenic site IV of F that crosslinks HRB and domain II, locking the prefusion conformation and blocking fusion. Fc-fused nanobodies were effective in vivo for both prophylaxis and treatment, nominating a structurally conserved, functionally essential epitope for next‑generation RSV biologics.
Impact: Defines a conserved, structurally validated fusion pivot epitope and delivers in vivo–active nanobody leads, advancing both mechanism and therapeutic development against RSV, including variants resistant to existing prophylaxis.
Clinical Implications: While preclinical, these data support development of inhaled or systemic nanobody biologics, potentially in combination with site Ø antibodies, to broaden prophylaxis, rescue resistance cases, and reduce dosing through high potency.
Key Findings
- Identified two nanobodies (1G9, 1D8) with high neutralization breadth against RSV subtypes and demonstrated prophylactic and therapeutic efficacy in vivo as Fc-fusions.
- Cryo-EM mapped binding to a conformational pivot within antigenic site IV, crosslinking HRB to domain II, stabilizing the prefusion conformation and preventing fusion.
- Epitope residues are highly conserved across RSV A/B, explaining broad-spectrum neutralization and nominating a pan-variant target.
Methodological Strengths
- High-resolution cryo-EM epitope mapping defining a novel functional pivot site with atomic detail
- In vivo validation of prophylactic and therapeutic efficacy of Fc-fused nanobodies
Limitations
- Preclinical study without human pharmacokinetic/immunogenicity or efficacy data
- Escape mutation risk and manufacturability of multivalent formats not fully assessed
Future Directions: Advance IND-enabling safety/PK studies, aerosol delivery optimization, and combination strategies with site Ø antibodies to minimize escape; evaluate durability and breadth against emerging RSV variants.
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants and elderly individuals. Although nirsevimab represents a recent breakthrough against RSV infection, the emergence of resistant variants highlight the need for additional antiviral strategies. Here, we report two nanobodies (Nbs), 1G9 and 1D8, that target the RSV fusion (F) protein and exhibit high neutralizing activity against RSV subtypes. In vivo, the Nbs-Fc demonstrated robust prophylactic and therapeutic efficacy. Cryo-electron microscopy revealed that 1G9 and 1D8 specifically engage a conformational pivot site within antigenic site IV, crosslinking the metastable heptad repeats B (HRB) and the conformationally stable domain II of the F protein. This interaction stabilizes the prefusion conformation and prevents the structural rearrangement required for membrane fusion. Notably, the binding residues are highly conserved across RSV subtypes, accounting for the broad-spectrum neutralization observed. Together, our findings identify a structurally conserved and functionally critical epitope on RSV F and highlight 1G9 and 1D8 as promising candidates for next-generation prophylactic and therapeutic interventions against RSV.
2. SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response.
Using recombinant mutant viruses and kinase knockout systems, the authors show SARS‑CoV‑2 relies on PERK‑dependent eIF2α phosphorylation to enforce nsp1‑mediated translation shutoff, whereas analogous MERS‑CoV nsp1 mutants rescue translation in WT cells. Both viruses’ nsp1 promote host mRNA decay, but SARS‑CoV‑2 suppresses GADD34 while MERS‑CoV induces it, revealing distinct ISR wiring.
Impact: Clarifies virus‑specific nsp1–ISR interactions that underlie host translation shutoff and mRNA decay, identifying PERK/eIF2α–GADD34 circuitry as modulators and potential antiviral targets.
Clinical Implications: Suggests therapeutic strategies that modulate PERK–eIF2α signaling or directly inhibit nsp1–ribosome interactions could differentially impact SARS‑CoV‑2 vs MERS‑CoV infections; informs rational ISR‑targeted antivirals.
Key Findings
- SARS‑CoV‑2 translation shutdown by nsp1 was rescued in PERK knockout but not PKR knockout cells, implicating PERK‑dependent p‑eIF2α.
- Analogous MERS‑CoV nsp1 mutants restored translation even in wild‑type cells, indicating mechanistic divergence from SARS‑CoV‑2.
- SARS‑CoV‑2 WT suppressed GADD34 whereas MERS‑CoV WT induced it; both viruses’ nsp1 promoted host mRNA degradation in WT but not nsp1‑mutant infections.
Methodological Strengths
- Use of recombinant coronaviruses with domain‑specific nsp1 mutations in parallel across species
- Genetic dissection with PERK/PKR knockout cells and single‑molecule FISH for host mRNA decay
Limitations
- Predominantly in vitro cellular systems; lack of in vivo pathogenesis validation
- Variant‑to‑variant variability in nsp1 function was not addressed
Future Directions: Test ISR‑modulating agents and nsp1 inhibitors in animal models; resolve structures of nsp1–host complexes; extend analyses to variant nsp1 alleles and primary airway systems.
Coronaviruses pose a serious threat to public health, driving the need for antiviral therapeutics and vaccines. Therefore, it is paramount to understand how this family of viruses evades cellular antiviral responses and establishes productive infection. The conserved coronavirus nonstructural protein 1 (nsp1) has been shown to inhibit host protein synthesis and, in some coronaviruses, promote host messenger RNA (mRNA) degradation while viral mRNAs are protected. We showed previously that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces activation of host integrated stress response (ISR) kinases protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), which promote phosphorylation of eukaryotic initiation factor 2 (eIF2α) and consequent inhibition of host protein synthesis. In contrast, eIF2α remains unphosphorylated during Middle East respiratory syndrome coronavirus (MERS-CoV) infection. To investigate the interactions of nsp1 and the ISR kinases, we utilized recombinant SARS-CoV-2 and MERS-CoV expressing nsp1 with mutations in each of two conserved domains. Upon infection with SARS-CoV-2 nsp1 mutants, translation was shut down in wildtype (WT) and PKR knockout (KO) cells but rescued in PERK KO cells, likely due to reduced p-eIF2α. In contrast, translation was rescued during infection with the analogous MERS-CoV nsp1 mutants even in WT cells. Moreover, SARS-CoV-2 WT suppressed expression of GADD34, a negative regulator of eIF2α phosphorylation, while SARS-CoV-2 nsp1 mutants induced GADD34. In contrast, MERS-CoV WT induced GADD34. Utilizing single-molecule fluorescence in situ hybridization, we found that SARS-CoV-2 and MERS-CoV nsp1 promote host mRNA degradation during WT, but not nsp1 mutant, infection. Thus, SARS-CoV-2 and MERS-CoV differ in interactions with the ISR and nsp1 control of host protein synthesis.
3. High-Flow Nasal Oxygen Therapy After Cardiac Surgery: A Randomized Clinical Trial.
In 1,280 adults at elevated pulmonary risk after nonemergent cardiac surgery, prophylactic HFNOT did not improve the primary outcome of days alive and at home without increased support over 90 days versus standard oxygen. Secondary outcomes were likewise similar, arguing against routine prophylactic HFNOT use post‑extubation in this setting.
Impact: A large, multicenter, assessor‑blinded RCT provides definitive negative evidence against routine prophylactic HFNOT after cardiac surgery, informing resource allocation and postoperative respiratory care pathways.
Clinical Implications: Avoid routine prophylactic HFNOT after nonemergent cardiac surgery; reserve HFNOT for treatment of established hypoxemic/ventilatory failure or as rescue therapy, potentially reducing costs and device burden.
Key Findings
- Primary outcome (DAH90 without increased support) showed no difference: median 0 days in both HFNOT and SOT groups (P = .75).
- Secondary outcomes, including DAH90 irrespective of added support, were similar between groups.
- Adaptive, multicenter RCT with concealed allocation and blinded outcome assessment across 17 centers supports non‑implementation of routine prophylactic HFNOT.
Methodological Strengths
- Large multicenter randomized design with concealed allocation and blinded outcome assessors
- Preplanned sample size re‑estimation and high follow‑up completeness (95.6%)
Limitations
- Primary endpoint (DAH90 without increased support) may be unfamiliar to some clinicians; effect on specific complications (e.g., reintubation) not highlighted in abstract
- Findings pertain to nonemergent surgeries; generalizability to emergent/complex cases may differ
Future Directions: Define subgroups that may benefit (e.g., specific ventilatory phenotypes), evaluate targeted HFNOT initiation criteria, and assess cost‑effectiveness in pragmatic implementations.
IMPORTANCE: High-flow nasal oxygen therapy (HFNOT) is used for noninvasive respiratory support following cardiac surgery despite uncertainty about its clinical effectiveness or associated costs. OBJECTIVE: To determine whether prophylactic HFNOT in patients at increased risk of respiratory complications following cardiac surgery has clinical benefits compared with standard oxygen therapy (SOT). DESIGN, SETTING, AND PARTICIPANTS: This adaptive, parallel group, randomized clinical trial collected and analyzed data from 17 cardiac surgery centers in 3 countries between October 7, 2020, and June 19, 2024. Eligible participants included adults undergoing nonemergent cardiac surgery with any of the following risk factors for pulmonary complications: chronic obstructive pulmonary disease, asthma, lower respiratory tract infection in the last 4 weeks, a body mass index of 35 or greater, or currently or recently smoking for longer than 10 pack-years. Outcome assessors were blinded. A preplanned sample size re-estimation was conducted after 300 participants completed the 90-day follow-up. INTERVENTION: Participants were randomized at a 1:1 ratio with concealed allocation to HFNOT or SOT administered for at least 16 hours immediately after postoperative extubation. MAIN OUTCOMES AND MEASURES: The primary effectiveness outcome was days alive and at home (DAH) without increased support compared with baseline in the first 90 days (DAH90). Any day of increased support, including at home, would provide a value of 0 for that day. Secondary outcomes included DAH90 without considering the additional support component. RESULTS: A total of 1280 patients were recruited (mean [SD] age, 62.9 [10.5] years; 892 [69.7%] men; 640 in each group), of whom 1224 (95.6%) had complete DAH90 data. The primary outcome of median DAH90 was 0 (IQR, 0-79) for the HFNOT group and 0 (IQR, 0-87) for the SOT group (median difference, 0 [95% CI, 0-0]; P = .75). Secondary clinical outcomes, including DAH90 without considering whether additional support was required, were similar between groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of HFNOT in patients at increased risk of postoperative pulmonary complications after nonemergent cardiac surgery, HFNOT did not improve DAH90 without increased support. These findings do not support the implementation of routine prophylactic HFNOT after cardiac surgery. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN14092678.