EBioMedicine最新文献

Background: The presence of cystic fibrosis (CF) in diverse groups is known but its incidence is not established in non-European populations. We predict that the number of births with CF in populations with non-European and European ancestry are comparable, and that sampling the general population may inform improved diagnostic and therapeutic strategies.

Methods: We curated pathogenic CFTR variants from the Genome Aggregation Database (gnomAD, versions 2.1 and 4.0) for different groups and estimated the incidence per 100,000 births using Hardy-Weinberg equilibrium. To estimate annual births with CF, we used United Nations population statistics. Additionally, we estimated the percentages of alleles missed by common screening panels and those not approved for treatment using highly effective modulator therapies (HEMT).

Findings: CF affects 44-52, 11-14, 7, 6, 4, and 0.2-1 births per 100,000 in European, African/African American, Admixed American, South Asian, East Asian, and Middle Eastern groups, respectively. Due to higher birth rates, the estimated annual births with CF in India (1426-1582) and Brazil (330-390) are comparable to those in the US (∼1000) and UK (∼300). The expanded Wisconsin screening panel misses the fewest variants in all groups (1-30% pathogenic alleles), while other screening panels miss 25->70% of pathogenic alleles from non-European groups. Of the pathogenic alleles in non-European groups, 25-40% were not approved for treatment using HEMT.

Interpretation: Absolute number of CF births in South America, Asia, and Africa may be comparable to those in the US and Europe. Improved diagnostics, therapeutics, and access to HEMT will benefit thousands of people with CF globally.

Funding: None.

Background: Neuroblastoma and Wilms tumour (WT) are common childhood embryonal malignancies. Germline 2p24 duplication has been reported in several cases of neuroblastoma and WT, either as part of a larger 2p duplication or as a microduplication involving just 2p24.3. Although the larger duplications involve many genes, including ALK, the microduplications have been localised to a region including MYCN and DDX1.

Methods: We analysed Whole Genome Sequence data from adults and children sequenced for various indications. We utilised a workflow to extract structural and copy number variants, filtered to include duplications or gains of 2 kb-20 Mb, including these loci, followed by manual inspection in IGV. Associations were assessed using Fisher's exact test. Penetrance was estimated by Bayesian calculation of the conditional probability of disease.

Findings: Among 113,431 genomes, there were 6 participants with a microduplication that included the MYCN locus. Of these, two had a diagnosis of WT and one of neuroblastoma. The 2p24.3 microduplication was therefore identified in 3/197 with a definite history of WT/neuroblastoma and 3/113,234 without such a history (p < 0.0001). Penetrance is estimated to be 13%. Twelve participants were identified with a 2p24.3 microduplication that included the DDX1 locus but not MYCN, none of whom received a diagnosis of a childhood embryonal tumour.

Interpretation: We have shown that 2p24.3 microduplications that include MYCN predispose to childhood embryonal tumours and should be routinely assessed when WT or neuroblastoma predisposition is suspected. We have also shown that there does not appear to be any increased incidence of childhood tumours when DDX1 alone is duplicated.

Funding: UCL Great Ormond Street Institute of Child Health Child Health Research CIO PhD Studentship, Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the National Institute for Health Research.

Background: The impact of CFTR modulator therapy on host immunity and outcomes in people with Cystic Fibrosis (CF)-related Aspergillus lung disease is poorly defined. We aimed to characterise fungal-relevant clinical outcomes post-CFTR modulators and assess effects on the Aspergillus-dependent Type I/III interferome.

Methods: Biomarkers of Aspergillus-related lung disease (Aspergillus-specific IgE/IgG), anti-fungal and corticosteroid therapy were analysed in a retrospective cohort of people with CF pre and post Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy. Homozygous F508del (CF) and CFTR TALEN-corrected bronchial epithelial cells (BECs) were challenged with Aspergillus conidia and hyphae in the presence or absence of ETI CFTR modulator therapy with bulk RNA transcriptomics and RT-PCR used to analyse Type I/III interferon genes. Effects of exogenous type I and III interferons on CF-neutrophil antifungal effector function was further characterised.

Findings: CFTR modulator (ETI) therapy was associated with a significant reduction in Aspergillus biomarkers alongside use of corticosteroid and anti-fungal therapy. In vitro Aspergillus stimulation enriched the Type I/III interferome in CFTR-corrected BECs compared to CF BECs, with ETI therapy partially restoring type I/III interferon gene expression in CF BECs. Administration of exogenous IFNλ1 increased anti-fungal killing in CF neutrophils without increased reactive-oxygen species or neutrophil extracellular trap production.

Interpretation: CFTR modulators have led to improved clinical outcomes in CF related Aspergillus-related lung disease potentially due to partial restoration of the host antifungal epithelial type I/III interferon response. Exogenous IFNλ1 further improved antifungal killing capacity of CF-neutrophils presenting a plausible future therapeutic strategy.

Funding: This study was funded by the Cystic Fibrosis Trust (SRC015).

Background: Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis.

Methods: We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis.

Findings: Our analysis revealed four genome-wide significant (p < 5 × 10^-8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant.

Interpretation: We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol.

Funding: This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.

Background: Fibroblast behaviour is a key determinant of outcomes in interstitial lung diseases (ILDs), yet mechanisms governing the switch between reversible repair and progressive fibrosis remain unclear. How disease-specific cellular niches shape fibroblast fate across ILD phenotypes has not been compared in situ.

Methods: We profiled peripheral lung tissues from controls, organising pneumonia (OP), connective tissue disease-associated ILD (CTD-ILD), and idiopathic pulmonary fibrosis (IPF) using High-Definition Visium spatial transcriptomics. A matched single-cell RNA-seq atlas was integrated via robust cell-type deconvolution to map cellular neighbourhoods. Differential expression and pathway activity were validated by immunofluorescence. Predicted ligand-receptor mechanisms and fibroblast responses were tested in vitro under glucocorticoid (GC), TGF-β1, and B-cell/MIF perturbations with receptor blockade.

Findings: Disease-specific niches were tightly coupled to fibroblast states. OP exhibited B-cell-AT2-myofibroblast-enriched niches with high GC responsiveness and apoptosis. IPF was dominated by bronchiolised epithelium, alongside myofibroblasts exhibiting glucocorticoid resistance and strong matrix programmes. CTD-ILD exhibited macrophage-rich niches with multinucleated giant cells. In vitro, GC induced NR3C1-mediated apoptosis in fibroblasts, whereas TGF-β1 drove a senescent, GC-resistant phenotype. IgD + B-cell-derived MIF enhanced fibroblast migration via CD74, an effect blunted by TGF-β1. Thus, niche composition dictates fibroblast fate, distinguishing GC-sensitive resolution from apoptosis-resistant fibrosis.

Interpretation: A GC-sensitive, apoptosis-prone myofibroblast niche in OP may underpin reversibility, whereas CTD-ILD and IPF follow distinct trajectories driven by immune dysregulation and epithelial-stromal maladaptation. These spatial microenvironmental signatures nominate therapeutic targets and may inform precision therapy for fibrotic lung disease.

Funding: The National Natural Science Foundation of China (82172109 to L.X., 82570001 to H.C.), the Ministry of Science and Technology of the People's Republic of China (2023YFC3502605, 2024YFA1108906) (H.C.), the Natural Science Foundation of Tianjin, China (25JCZDJC01260) (H.C.); the Key Laboratory of Medical Rescue Key Technology and Equipment, Ministry of Emergency Management (Open Fund Project No. YJBKFKT202410).

Background: This systematic review examined the duration of measles virus airborne transmissibility after a source case is no longer present to identify evidence gaps in measles contact tracing exposure window guidelines.

Methods: A systematic literature review following PRISMA guidelines was conducted using PubMed, EMBASE, Web of Science, and SCOPUS databases for publications from January 1988 to July 2024. Additional sources were identified through reference list reviews and Google Scholar searches. Studies examining how long the measles virus survives in the air or remains transmissible after an infectious case leaves a public space were included, while editorials, opinion pieces, non-evidence-based recommendations, mathematical models, and publications unrelated to airborne transmission of measles in public environments or not available in English were excluded. Researchers extracted summary data.

Findings: Initial database searches identified 1054 studies, with none meeting initial inclusion criteria after screening. Supplemental searches identified five relevant articles (1964-1987). Two experimental studies and three real-world studies demonstrated measles virus survival between 29 and 120 min, with increasing survival time for lower humidity levels.

Interpretation: Current guidelines for measles contact tracing exposure windows rely on limited research from 1964 to 1987. Additional studies are urgently needed to understand how long the virus is transmissible in real-world settings, particularly given the implications for contact tracing efficiency and resource allocation during outbreak responses.

Funding: U.S. Centers for Disease Control & Prevention (Cooperative Agreement #NU38FT000004).

Background: The COVID-19 pandemic underscored how hospital-acquired co-infections with antimicrobial resistance (AMR) bacteria and respiratory viruses can drive high mortality in critically ill patients. Despite antimicrobial stewardship and vaccines, effective prophylactic solutions remain lacking, highlighting the need for safe, antigen-independent strategies that provide rapid, broad-spectrum protection.

Methods: We tested whether a single intraperitoneal pretreatment with n-dodecyl-β-D-maltoside (DDM) could provide broad prophylaxis. Mice were challenged with clinical isolates of carbapenem-resistant Escherichia coli (CREC) and Pseudomonas aeruginosa (CRPA), methicillin-resistant Staphylococcus aureus (MRSA), or pandemic H1N1 influenza. Mechanistic studies assessed intracellular bacterial killing, immune cell dynamics (flow cytometry, histopathology), and neutrophil depletion, transcriptome, and cytokine profiling.

Findings: A single prophylactic administration of DDM conferred complete protection against lethal CREC, CRPA, and MRSA, while reducing viral titres and mortality in influenza-infected mice. DDM primed innate immunity through rapid neutrophil recruitment and activation, enhancing phagocytosis, bacterial clearance, and expression of effector genes linked to chemotaxis, ROS, and NET formation, predominantly mediated by Gi-dependent signalling pathway. Unlike pathogen-associated molecular pattern (PAMP)-based agents, DDM did not induce systemic inflammation or long-term immune reprogramming. Neutrophil depletion abolished protection, confirming their central role. Furthermore, DDM upregulated interferon-stimulated genes in lung tissue only upon viral infection, conferring selective antiviral immunity while attenuating cytokine-driven pathology.

Interpretation: DDM is a first-in-class, non-PAMP immune primer that rapidly and safely induces neutrophil-driven protection against AMR bacterial sepsis and viral infection, offering a host-directed strategy for cross-pathogen prophylaxis in high-risk settings.

Funding: National Research Foundation of Korea (RS-2023-00219213); Korea Environmental Industry and Technology Institute (2022002980009; 1485018881); Korea Research Institute of Bioscience and Biotechnology Research Initiative Program.