EBioMedicine最新文献

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.

Background: Tumour associated macrophages (TAMs) and exhausted T cells are dominant in the immuno-suppressive tumour microenvironment (TME) and pose a challenge to effective cancer immunotherapy in solid tumours.

Methods: In this study, we immunised llamas and generated monovalent and biparatopic nanobodies (Nbs) against colony stimulating factor 1 receptor (CSF-1R) and programmed death receptor 1 (PD-1) to re-educate TAMs and overcome T cell exhaustion, respectively, in the TME. To circumvent short systemic half-life and low peak concentrations of Nbs in the TME, we developed a platform of allogenic off-the-shelf stem cells (SC) releasing biparatopic PD-1 and CSF-1R Nbs and tested its efficacy in different mouse models.

Findings: Nbs targeting CSF-1R and PD-1 inhibited the CSF1/CSF-1R and PD-1/PD-L1 pathways, respectively, with biparatopic Nbs demonstrating superior efficacy and functionality compared with their monovalent counterparts. Locoregional SC mediated release of biparatopic CSF-1R and PD-1 Nbs, reduced tumour growth by increasing T cell numbers, enhancing T cell activation, and by shifting the macrophage polarisation towards a pro-inflammatory phenotype. Moreover, the presence of both Nbs improved dendritic cells (DCs) activation within the TME. Finally, we show that biocompatible gel encapsulated SC releasing Nbs against PD-1 and CSF-1R have therapeutic efficacy in a highly immunosuppressive glioblastoma model post-tumour resection.

Interpretation: Taken together, our findings establish a cell-based Nb platform targeting both innate and adaptive immune axis within the TME, which has the potential to facilitate treatment of solid cancers that are otherwise refractory to conventional immunotherapies.

Funding: This study was mainly supported by Institutional Funds (K.S). A part of in vivo Nb characterisation was supported by NIH grant R01-CA285519 (K.S.) and the Nb dye conjugation and modelling was supported by NIH grant R01-AI165666 (M.R).

Background: Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden.

Methods: In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning.

Findings: Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines.

Interpretation: MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS.

Funding: NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.

Background: Hunger is commonly linked to negative mood, and mood shifts are believed to arise from sensing the body's internal state. However, it remains unclear whether this link is driven by subconscious effects of circulating glucose levels or by consciously sensed metabolic states. Here, we test whether glucose levels directly influence mood or indirectly via subjective ratings of metabolic state.

Methods: In this observational cohort study, 90 healthy adults (female = 46; male = 44) were continuously monitored throughout the day using interstitial glucose sensors for four weeks while completing ecological momentary assessments up to twice per day (EMA; M = 48 assessments per participant) to rate mood and perceived metabolic states.

Findings: As expected, hungry participants reported lower mood, and metabolic state ratings were associated with glucose levels. Although glucose levels were associated with mood, the metabolic state ratings mediated this association. Individual differences reflecting metabolic health (i.e., BMI and insulin resistance) did not affect the interaction between glucose and metabolic state ratings on mood. Notably, individuals with higher interoceptive accuracy had fewer fluctuations in mood ratings.

Interpretation: We conclude that hunger-related mood shifts depend on conscious sensing of the body's internal state instead of acting subconsciously. Our study highlights the relevance of considering the self-report of bodily signals in understanding mood shifts, offering new fundamental insights into mood regulation mechanisms.

Funding: The study was supported by the German Research Foundation (DFG) grants KR 4555/7-1, KR 4555/9-1, KR 4555/10-1, and DE 2319/22-1.

Background: Long term respiratory symptoms are reported following recovery of acute COVID-19 infection and residual lung abnormalities (RLA) on follow-up thoracic computed tomography (CT) after COVID-19 hospitalisation have been observed. It is unknown whether RLA are associated with epithelial lung injury.

Methods: Plasma was sampled from the observational Post HOSPitalisation-COVID cohort at five months post-hospitalisation. Epithelial injury biomarkers Krebs von den Lungen-6 (KL-6), matrix metalloproteinase 7 (MMP-7), surfactant protein-D (SP-D) and surfactant protein-A (SP-A) were assayed. In those without follow-up CT, RLA at-risk was defined by percent predicted DL_CO <80% and/or abnormal chest X-ray, otherwise they were considered low-risk. Follow-up CT RLA was defined as combined involvement of ground glass opacity and reticulation ≥10%.

Findings: A total of 957 people were included, 846 people with no CT (at-risk n = 103; 12.2%), 111 people with follow-up CT (RLA ≥10% n = 85; 76.6%). All epithelial injury biomarkers were significantly elevated in people at-risk of RLA compared with low-risk. KL-6 and MMP-7 were significantly higher in people with ≥10% RLA than those with <10%, SP-D and SP-A did not reach significance. SP-D and SP-A were associated with percent involvement of reticulation (3.22%, 95% CI 1.19-5.24; 3.03%, 95% CI 0.76-5.30, respectively).

Interpretation: RLA after acute COVID-19 infection were consistent with elevated epithelial injury biomarkers and pro-fibrotic signalling. Future studies should address the temporal association between fibrotic biomarkers and resolution or progression of radiological involvement.

Funding: MRC-UK Research and Innovation and National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19 (MR/V027859/1; COV0319; MR/W006111/1).