Disease Models & Mechanisms最新文献_第4页

Infectious Disease: Evolution, Mechanism and Global Health. 传染病：进化、机制和全球健康。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-10-17 DOI: 10.1242/dmm.052701

Rachel Hackett, Judith E Allen, Sumana Sanyal, David M Tobin, Russell Vance

引用次数: 0

The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation. 25-羟基胆固醇在与感染和胆固醇失调相关的脑血管功能障碍病理生理学中的作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-05-23 DOI: 10.1242/dmm.052145

Victor S Tapia, Sarah E Withers, Ran Zhou, Abigail Bennington, Christopher Hoyle, Frances Hedley, Adam El Khouja, Nadim Luka, Marco Massimo, Siobhan Crilly, Katherine R Long, Catherine B Lawrence, Paul R Kasher

{"title":"The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation.","authors":"Victor S Tapia, Sarah E Withers, Ran Zhou, Abigail Bennington, Christopher Hoyle, Frances Hedley, Adam El Khouja, Nadim Luka, Marco Massimo, Siobhan Crilly, Katherine R Long, Catherine B Lawrence, Paul R Kasher","doi":"10.1242/dmm.052145","DOIUrl":"10.1242/dmm.052145","url":null,"abstract":"The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates cholesterol metabolism during infection, have been associated with vascular pathology. Viral infections have been linked to intracerebral haemorrhage (ICH) risk, but the molecular mechanisms leading to ICH via antiviral responses remain unknown. We hypothesised that the CH25H/25HC pathway impacts neuroendothelial integrity in the context of infection-associated ICH. Using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced zebrafish ICH model and foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified upregulation of CH25H in infection-associated cerebral haemorrhage. Using zebrafish models and human brain endothelial cells, we asked whether 25HC promotes neurovascular dysfunction by modulating cholesterol metabolism. We found that 25HC and pharmacological inhibition of cholesterol synthesis had an additive effect to exacerbate brain bleeding in zebrafish and in vitro neuroendothelial dysfunction. 25HC-induced dysfunction was also rescued by cholesterol supplementation in vitro. These results demonstrate that 25HC can dysregulate brain endothelial function by remodelling cholesterol metabolism. We propose that CH25H/25HC plays an important role in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation in the context of ICH.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"18 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An alveolus lung-on-a-chip model of Mycobacterium fortuitum lung infection. 福氏分枝杆菌肺部感染肺泡肺芯片模型的建立。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-08-01 DOI: 10.1242/dmm.052085

Victoria Ektnitphong, Beatriz R S Dias, Priscila C Campos, Michael U Shiloh

{"title":"An alveolus lung-on-a-chip model of Mycobacterium fortuitum lung infection.","authors":"Victoria Ektnitphong, Beatriz R S Dias, Priscila C Campos, Michael U Shiloh","doi":"10.1242/dmm.052085","DOIUrl":"10.1242/dmm.052085","url":null,"abstract":"Lung disease due to non-tuberculous mycobacteria (NTM) is rising in incidence. Although both two-dimensional cell culture and animal models exist for NTM infections, a major knowledge gap is the early responses of human alveolar and innate immune cells to NTM within the human alveolar microenvironment. Here, we describe the development of a humanized, three-dimensional, alveolus lung-on-a-chip (ALoC) model of Mycobacterium fortuitum lung infection that incorporates only primary human cells, such as pulmonary vascular endothelial cells, in a vascular channel, and type I and II alveolar cells and monocyte-derived macrophages in an alveolar channel along an air-liquid interface. M. fortuitum introduced into the alveolar channel primarily infected macrophages, with rare bacteria inside alveolar cells. Bulk RNA sequencing of infected chips revealed marked upregulation of transcripts for cytokines, chemokines and secreted protease inhibitors (SERPINs). Our results demonstrate how a humanized ALoC system can identify critical early immune and epithelial responses to M. fortuitum infection. We envision potential application of the ALoC to other NTM and in studies of new antibiotics.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unravelling γδ T-cell dysregulation in the gut and its implications for immune-mediated diseases. 肠道γδ t细胞失调及其对免疫介导疾病的影响

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-09-18 DOI: 10.1242/dmm.052439

Dilys Santillo, Evangelos Bellos, Vanessa Sancho-Shimizu

引用次数: 0

A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity. TOM1 G307D变体损害与TOLLIP的相互作用，自噬体-溶酶体融合和先天免疫调节。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-09-30 DOI: 10.1242/dmm.052140

Heljä K M Lång, Tiffany G Roach, Maarit Hölttä, Salla Keskitalo, Markku Varjosalo, Kaarina Heiskanen, Megan V Collins, Mikko R J Seppänen, Daniel G S Capelluto, Elina Ikonen, Samppa J Ryhänen

{"title":"A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity.","authors":"Heljä K M Lång, Tiffany G Roach, Maarit Hölttä, Salla Keskitalo, Markku Varjosalo, Kaarina Heiskanen, Megan V Collins, Mikko R J Seppänen, Daniel G S Capelluto, Elina Ikonen, Samppa J Ryhänen","doi":"10.1242/dmm.052140","DOIUrl":"10.1242/dmm.052140","url":null,"abstract":"A recently described G307D variant of the endosomal adaptor protein TOM1 causes severe early-onset multiorgan autoimmunity and combined immunodeficiency. By combining biophysical, biochemical and cell culture experiments, we show that the variant causes a defect in the interaction between TOM1 and TOLLIP, another adaptor protein involved in cargo trafficking and regulation of innate immunity. The G307D variant impairs the ability of TOM1 to reduce TOLLIP phosphatidylinositol 3-phosphate binding, an important regulatory mechanism for cargo trafficking commitment for both proteins. Our experiments using TOM1 G307D patient cells suggested that the variant affects autophagy, seen as an aggravated response to amino acid starvation and accumulation of autophagosomes due to autophagosome-lysosome fusion defect. In addition, inflammatory pathways showed excessive activation in TOM1 G307D patient cells. Our data suggest that the interaction between TOM1 and TOLLIP has a role in the regulation of the human immune system and highlight the importance of fundamental cellular functions, such as cargo trafficking, in controlling immune responses. Our study also provides insights into the caveats of immunomodulatory and stem cell therapies in patients with TOM1 pathogenic variants.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A subset of neutrophil phagosomes is characterised by pulses of Class I PI3K activity. 中性粒细胞吞噬体的一个子集以一类PI3K活性脉冲为特征。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-08-29 DOI: 10.1242/dmm.052042

Clare F Muir, Constantino Carlos Reyes-Aldasoro, Tomasz K Prajsnar, Bartosz J Michno, Justyna Cholewa-Waclaw, Yin X Ho, Audrey Bernut, Catherine A Loynes, Stone Elworthy, Kieran A Bowden, Ashley J Cadby, Lynne R Prince, Jason S King, Felix Ellett, Alison M Condliffe, Stephen A Renshaw

{"title":"A subset of neutrophil phagosomes is characterised by pulses of Class I PI3K activity.","authors":"Clare F Muir, Constantino Carlos Reyes-Aldasoro, Tomasz K Prajsnar, Bartosz J Michno, Justyna Cholewa-Waclaw, Yin X Ho, Audrey Bernut, Catherine A Loynes, Stone Elworthy, Kieran A Bowden, Ashley J Cadby, Lynne R Prince, Jason S King, Felix Ellett, Alison M Condliffe, Stephen A Renshaw","doi":"10.1242/dmm.052042","DOIUrl":"10.1242/dmm.052042","url":null,"abstract":"Class I PI3 kinases (PI3Ks) coordinate the delivery of microbicidal effectors to the phagosome by forming phosphatidylinositol (3,4,5)-trisphosphate (PIP3). However, the dynamics of PIP3 in neutrophils during a live bacterial tissue infection are unknown. We therefore developed an in vivo, live zebrafish infection model that enables visualisation of dynamic changes in Class 1 PI3K signalling in neutrophil phagosomes in real time. We identified that, on ∼12% of neutrophil phagosomes, PHAkt-eGFP, a reporter for Class 1 PI3K signalling, repeatedly fades and re-recruits in pulsatile bursts. This phenomenon occurred on phagosomes containing live and dead bacteria as well as beads, and was dependent on the activity of the Class 1 PI3K isoform PI3Kγ. Detailed imaging suggested that pulsing phagosomes represent neutrophils transiently re-opening and re-closing phagosomes, a conclusion supported by observations that a subset of phagosomes in human neutrophils rapidly accumulate dye from the extracellular space. Therefore, we propose that some neutrophil phagosomes remain unsealed and are consequently able to exchange contents with the extracellular environment, with implications for phagosome fate and communication with surrounding cells.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12444860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The inflammasome adaptor pycard is essential for immunity against Mycobacterium marinum infection in adult zebrafish. 炎性小体接头pycard对成年斑马鱼对海洋分枝杆菌感染的免疫至关重要。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-24 DOI: 10.1242/dmm.052061

Meri Uusi-Mäkelä, Sanna-Kaisa Emilia Harjula, Maiju Junno, Alina Sillanpää, Reetta Nätkin, Mirja Tellervo Niskanen, Anni Karoliina Saralahti, Matti Nykter, Mika Rämet

{"title":"The inflammasome adaptor pycard is essential for immunity against Mycobacterium marinum infection in adult zebrafish.","authors":"Meri Uusi-Mäkelä, Sanna-Kaisa Emilia Harjula, Maiju Junno, Alina Sillanpää, Reetta Nätkin, Mirja Tellervo Niskanen, Anni Karoliina Saralahti, Matti Nykter, Mika Rämet","doi":"10.1242/dmm.052061","DOIUrl":"10.1242/dmm.052061","url":null,"abstract":"Inflammasomes regulate the host response to intracellular pathogens including mycobacteria. We have previously shown that the course of Mycobacterium marinum infection in adult zebrafish (Danio rerio) mimics the course of tuberculosis in human. To investigate the role of the inflammasome adaptor pycard in zebrafish M. marinum infection, we produced two zebrafish knockout mutant lines for the pycard gene with CRISPR/Cas9 mutagenesis. Although the zebrafish larvae lacking pycard developed normally and had unaltered resistance against M. marinum, the loss of pycard led to impaired survival and increased bacterial burden in the adult zebrafish. Based on histology, immune cell aggregates, granulomas, were larger in pycard-deficient fish than in wild-type controls. Transcriptome analysis with RNA sequencing of a zebrafish haematopoietic tissue, kidney, suggested a role for pycard in neutrophil-mediated defence, haematopoiesis and myelopoiesis during infection. Transcriptome analysis of fluorescently labelled, pycard-deficient kidney neutrophils identified genes that are associated with compromised resistance, supporting the importance of pycard for neutrophil-mediated immunity against M. marinum. Our results indicate that pycard is essential for resistance against mycobacteria in adult zebrafish.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Patient advocacy in tuberculosis research and treatment: an interview with Zolelwa Sifumba. 结核病研究和治疗中的患者倡导：对Zolelwa Sifumba的采访。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-19 DOI: 10.1242/dmm.052316

Zolelwa Sifumba

引用次数: 0

A BALB/c mouse model of Mycobacterium abscessus lung infection based on once-weekly cyclophosphamide administration. 基于每周一次环磷酰胺给药的脓肿分枝杆菌肺部感染BALB/c小鼠模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-05-29 DOI: 10.1242/dmm.052310

Binayak Rimal, Chandra M Panthi, Ruth A Howe, Gyanu Lamichhane

{"title":"A BALB/c mouse model of Mycobacterium abscessus lung infection based on once-weekly cyclophosphamide administration.","authors":"Binayak Rimal, Chandra M Panthi, Ruth A Howe, Gyanu Lamichhane","doi":"10.1242/dmm.052310","DOIUrl":"10.1242/dmm.052310","url":null,"abstract":"Mycobacterium abscessus is a fast-growing non-tuberculous mycobacterium that can cause chronic lung disease leading to rapid decline in lung function. There are no FDA-approved therapies for this disease. To support the development of new treatments, an animal model of M. abscessus lung infection that is simple to implement and requires minimal resources is crucial to encourage broad adoption. We present a mouse model using the immunocompetent BALB/c strain, which is both widely available and cost effective. Since BALB/c mice naturally clear M. abscessus infections, immunosuppression is necessary to sustain bacterial growth in the lungs. Once-weekly intraperitoneal injections of the immunosuppressant cyclophosphamide at 250 mg/kg successfully induced proliferation of M. abscessus during the acute phase, followed by stabilization characteristic of chronic infection. This model demonstrated the efficacy of imipenem - an antibiotic commonly used in clinical settings - by significantly reducing bacterial burdens, mirroring their effects in human cases. However, clofazimine, which is also used to treat this disease, was bacteriostatic. This cost-effective and accessible mouse model is suitable for diverse laboratory environments and provides a valuable tool for preclinical evaluation of treatments for M. abscessus lung disease.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuroinflammation in fungal infections: from pathogen recognition to pathological manifestations. 真菌感染中的神经炎症：从病原体识别到病理表现。

IF 3.3 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-10-09 DOI: 10.1242/dmm.052344

Rachael Dangarembizi, Amalia Awala, Anja de Lange

引用次数: 0