Respiratory - Papers

Two European bat MERS-related coronaviruses use ACE2 via a binding interface located >45 Å from any previously known ACE2 footprint. Broad ACE2 ortholog screening identified key host tropism determinants, including ACE2 N432 glycosylation, and enabled the design of a potent soluble bat ACE2 decoy that neutralizes these viruses.

HKU5 coronaviruses use ACE2 via a novel binding mode and can be enabled to use human ACE2 by a single amino acid change. The study maps species tropism determinants, identifies small-molecule inhibitors (including clinical compounds), and highlights antigenic divergence from MERS-CoV, informing outbreak preparedness.

Cross-species single-cell and regulatory analyses show that much of the genetic program for lungs existed before the emergence of bony fish, with later acquisition of lung-specific enhancers and mammal-specific alveolar innovations. Alveolar type 1 cells are mammal-specific, and sfta2 deletion causes severe respiratory defects in mice, establishing function for a new lung gene.

This multi-center mechanistic study identifies a link between Epstein–Barr virus (EBV) and multisystem inflammatory syndrome in children (MIS-C) mediated by TGF-β signaling. The work delineates immune pathways connecting prior viral exposures to post–SARS-CoV-2 hyperinflammation in pediatric patients, highlighting potential biomarkers and therapeutic targets.

Integrating plasma metabolomics and whole-blood transcriptomics from 160 ARDS patients in the ROSE trial, the authors identified four mortality-linked molecular signatures spanning innate activation/glycolysis, hepatic-immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell-cycle programs. Mitochondrial dysfunction emerged as a unifying feature across phenotypes, and all signatures were validated in an independent sepsis cohort.

A bat HKU5-CoV lineage 2 virus was identified that efficiently uses human ACE2, with a receptor-binding footprint overlapping sarbecoviruses. Authentic virus infected hACE2 cell lines and human respiratory/enteric organoids, indicating broad tropism and enhanced adaptation versus lineage 1. These findings elevate the zoonotic risk profile of merbecoviruses.

In this randomized, placebo-controlled human challenge trial, BPZE1 prevented or substantially reduced colonization by virulent Bordetella pertussis. In the per-protocol adequate inoculum population, 60% of BPZE1 recipients versus 25% of placebo had no detectable colonization on days 9, 11, and 14 post-challenge (p=0.033). Safety was favorable with mostly mild local/systemic events and no serious adverse events.

This mechanistic study shows macrophage peroxisomes as regulators of inflammation resolution and alveolar regeneration during severe respiratory viral infection. Peroxisome integrity supports lipid metabolism, mitochondrial health, and restrains inflammasome/IL-1β, thereby limiting pathological alveolar transitional cell accumulation after SARS-CoV-2.

Using single-cell RNA sequencing of nasopharyngeal swabs from vaccinated and unvaccinated adults across ancestral, Delta, and Omicron waves, the study shows that Delta and Omicron infections share similar nasal cellular compositions, with myeloid and T cell populations and viral transcripts driving patterns. The integrated dataset illuminates how variants and vaccination status shape mucosal immune landscapes.

Using in situ cryo-electron tomography, the authors directly mapped the native structures and spatial organization of mitochondrial respiratory complexes in intact cells. These data inform how electron transport and proton pumping may be coordinated in vivo and provide a structural foundation for understanding respiratory efficiency and disease.

This study identifies a lung 'pro-thrombotic niche' where CXCL13-reprogrammed interstitial macrophages secrete small EVs carrying clustered integrin β2, which promote thrombosis and metastasis. It mechanistically links lung microenvironment-derived EVs to systemic thromboinflammation in cancer, highlighting ITGB2 and CXCL13 axes as therapeutic targets.

The authors generated human ACE2 transgenic pigs that support productive SARS-CoV-2 infection and exhibit hallmark clinical signs and lung immunopathology mirroring severe human COVID-19. Viral replication was detected in upper and lower airways through day 7 post-infection.

This study identifies MFSD6 as the cellular entry receptor for enterovirus D68, a respiratory pathogen associated with acute flaccid myelitis. The finding provides a mechanistic basis for host tropism and opens therapeutic avenues to block viral entry.

In 122 stage I NSCLC patients (57 recurrent), integrated genomics/epigenomics/transcriptomics linked solid/micropapillary histology, genomic instability, and APOBEC signatures to recurrence. PRAME was hypomethylated and overexpressed; hypomethylation at a TEAD1 site enabled PRAME transcription, and PRAME inhibition reduced metastasis via EMT gene downregulation. Multi-omics clustering stratified patients into four subgroups with distinct recurrence risks and therapeutic vulnerabilities.

A multi-omic atlas across histological stages of diffuse alveolar damage in COVID-19 reveals early interferon/metallothionein programs and late pro-fibrotic collagen signatures, with endothelial SERPINE1/PAI-1 upregulation suggesting fibrinolytic shutdown. Macrophage-derived SPP1 signaling emerges as a key early regulator.

Barcoded H1N1 infections in ferrets revealed that the nasal cavity and trachea maintain highly diverse viral populations conducive to adaptation, whereas the lungs exhibit pauci-clonal, genetically distinct populations due to seeding bottlenecks. Inoculation route modulated lung population structure, and barcode diversity declined over time as de novo variants arose locally, driving divergence across sites.

Inflammation-driven cathepsin K cleaves angiopoietin-2 into 25/50 kDa fragments that antagonize Tie2, destabilizing the endothelium in sepsis. Pharmacologic inhibition with odanacatib improved survival in murine models, and ANGPT2 fragments accumulated in septic patients and associated with worse outcomes.

In aged tumor-bearing mice, anti–PD-(L)1 therapy induces ICOS+ CD4+ T cell activation that drives germinal center B cell responses and lung injury mimicking irAEs; blocking ICOS–ICOSL attenuates damage, while local IL-21 restores it. Adoptive transfer and single-cell data show both aged host milieu and pathogenic CD4+ T cells are required. In patients, CD4+ T-cell ICOS upregulation correlates with later irAE incidence.

Cryo-EM structures reveal that sub-stoichiometric bortezomib binding activates M. tuberculosis ClpP1P2, drives chaperone recruitment (ClpC1/ClpX), and uncovers a substrate channel gating mechanism. These insights connect a clinically approved proteasome inhibitor to actionable regulation of a validated TB target.

XYLT1 is upregulated in metastatic recurrent early-stage lung adenocarcinoma and promotes metastasis by enabling sGAG conjugation of IκBα, enhancing its proteasomal degradation and activating NF-κB signaling. The study links proteoglycan modification to a canonical inflammatory pathway as a driver of metastasis, offering biomarker and therapeutic target opportunities.

The authors identify MFSD6 as a functional EV-D68 entry receptor that mediates viral attachment. An MFSD6-Fc recombinant decoy blocks uptake and infection in vitro and protects newborn mice from lethal challenge, highlighting a druggable entry mechanism.

Using allergen inhalation and reporter mice, the authors show that IgE class switching occurs predominantly within the lung and that lung-resident memory B cells—likely IgG1+ MBCs—maintain airway IgE responses. This identifies a local memory circuit sustaining allergic disease in the respiratory tract.

This mechanistic study shows that CXCL8 engagement of CXCR1/2 activates MAPK signaling, driving hnRNP‑K cytoplasmic translocation and enhanced recognition of viral RNA, thereby promoting EV‑D68 replication, with similar effects in influenza and rhinovirus. Genetic or pharmacologic disruption of CXCL8/CXCR1/2 reduces viral replication in vitro, positioning the axis as a potential pan‑respiratory antiviral target.

This mechanistic study identifies KMT2A as an epigenetic driver of pulmonary fibrosis that upregulates PU.1 in fibroblasts via H3K4me3, thereby promoting fibrogenesis. Genetic knockdown, fibroblast-specific PU.1 deletion, and a KMT2A complex inhibitor (mm102) each attenuated bleomycin-induced fibrosis, nominating KMT2A→PU.1 as a targetable axis.