Disease Models & Mechanisms最新文献

Reduced growth and biofilm formation at high temperatures contribute to Cryptococcus deneoformans dermatotropism. 在高温下减少生长和生物膜的形成有助于变形隐球菌的皮肤偏向性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-25 DOI: 10.1242/dmm.052141

Claudia L Charles-Niño, Gunjan M Desai, Nicholas Koroneos, Mohamed F Hamed, Neena Jain, William Lopes, Anthony Braswell, Alexander Linares, Melissa E Munzen, Joshua D Nosanchuk, Marilene H Vainstein, Luis R Martinez

{"title":"Reduced growth and biofilm formation at high temperatures contribute to Cryptococcus deneoformans dermatotropism.","authors":"Claudia L Charles-Niño, Gunjan M Desai, Nicholas Koroneos, Mohamed F Hamed, Neena Jain, William Lopes, Anthony Braswell, Alexander Linares, Melissa E Munzen, Joshua D Nosanchuk, Marilene H Vainstein, Luis R Martinez","doi":"10.1242/dmm.052141","DOIUrl":"10.1242/dmm.052141","url":null,"abstract":"Cryptococcus deneoformans (Cd) and C. neoformans (Cn) differ in geographic prevalence and dermatotropism, with Cd strains more commonly isolated from temperate regions and skin infections. Rising global temperatures prompt concerns regarding selection for environmental fungal species with increased thermotolerance, as high mammalian temperatures provide protection against many fungal species. Cd and Cn strains exhibit variations in thermal susceptibility, with Cd strains being more susceptible to higher temperatures. Here, we identified differences in capsular polysaccharide release, adhesion and biofilm formation between strains both in vivo and in vitro. Histological results suggested that the dermatotropic predilection associated with Cd relates to biofilm formation, possibly facilitating latency and extending fungal survival through protection from high temperatures. We demonstrated that Cn strains were more tolerant to mammalian and febrile temperatures than Cd strains. Similarly, Cd strains showed reduced expression of heat-shock protein 60 and 70, after prolonged exposure to high temperature. Our findings suggest that fungal adhesion, biofilm formation, inflammation and thermotolerance contribute to tissue tropism and disease manifestation by Cn and Cd, supporting the recently assigned species distinction to each of these serotypes.","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/PMC11972076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603803","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

Translational lessons from the balanced immune system in bats. 蝙蝠平衡免疫系统的翻译经验。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-02-19 DOI: 10.1242/dmm.050763

Wei Lun Ng, Lin-Fa Wang

引用次数: 0

Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19. 将SARS-CoV-2感染动物模型转化为COVID-19的血管、神经和胃肠道表现。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-04-08 DOI: 10.1242/dmm.052086

James Chung, Julia Pierce, Craig Franklin, Rachel M Olson, Alan R Morrison, James Amos-Landgraf

{"title":"Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19.","authors":"James Chung, Julia Pierce, Craig Franklin, Rachel M Olson, Alan R Morrison, James Amos-Landgraf","doi":"10.1242/dmm.052086","DOIUrl":"10.1242/dmm.052086","url":null,"abstract":"Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 million deaths, it has become evident that COVID-19 is not solely a pulmonary disease. Emerging evidence has shown that, in a subset of patients, certain symptoms - including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain - all indicate a role of vascular, neurological and gastrointestinal (GI) pathology in the disease process. Many of these disease processes persist long after the acute disease has been resolved, resulting in 'long COVID' or post-acute sequelae of COVID-19 (PASC). The molecular mechanisms underlying the acute and systemic conditions associated with COVID-19 remain incompletely defined. Appropriate animal models provide a method of understanding underlying disease mechanisms at the system level through the study of disease progression, tissue pathology, immune system response to the pathogen and behavioral responses. However, very few studies have addressed PASC and whether existing models hold promise for studying this challenging problem. Here, we review the current literature on cardiovascular, neurological and GI pathobiology caused by COVID-19 in patients, along with established animal models of the acute disease manifestations and their prospects for use in PASC studies. Our aim is to provide guidance for the selection of appropriate models in order to recapitulate certain aspects of the disease to enhance the translatability of mechanistic studies.","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/PMC12010913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802718","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

Correlative 3D imaging method for analysing lesion architecture in susceptible mice infected with Mycobacterium tuberculosis. 相关三维成像方法分析易感小鼠结核分枝杆菌病变结构。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-03-26 DOI: 10.1242/dmm.052185

Caroline G G Beltran, Jurgen Kriel, Stefan M Botha, Margaret B Nolan, Alessandro Ciccarelli, Ben Loos, Maximiliano G Gutierrez, Gerhard Walzl

{"title":"Correlative 3D imaging method for analysing lesion architecture in susceptible mice infected with Mycobacterium tuberculosis.","authors":"Caroline G G Beltran, Jurgen Kriel, Stefan M Botha, Margaret B Nolan, Alessandro Ciccarelli, Ben Loos, Maximiliano G Gutierrez, Gerhard Walzl","doi":"10.1242/dmm.052185","DOIUrl":"10.1242/dmm.052185","url":null,"abstract":"Tuberculosis (TB) is characterized by the formation of heterogeneous, immune-rich granulomas in the lungs. Host and pathogen factors contribute to this heterogeneity, but the molecular and cellular drivers of granuloma diversity remain inadequately understood owing to limitations in experimental techniques. In this study, we developed an approach that combines passive CLARITY (PACT)-based clearing with light-sheet fluorescence microscopy to visualize lesion architecture and lung involvement in Mycobacterium tuberculosis-infected C3HeB/FeJ mice. Three-dimensional rendering of post-mortem lungs revealed critical architectural features in lesion development that traditional thin-section imaging could not detect. Wild-type M. tuberculosis infection resulted in organized granulomas, with median sizes increasing to 3.74×108 µm3 and occupying ∼10% of the total lung volume by day 70 post-infection. In contrast, infection with the avirulent ESX-1 deletion mutant strain resulted in diffuse and sparsely organized CD11b recruitment (median size of 8.22×107 µm3), primarily located in the lung periphery and minimally involving the airways (0.23% of the total lung space). Additionally, we present a method for volumetric correlative light and electron microscopy, enabling tracking of individual immune cell populations within granulomas.","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/PMC11972079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708435","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 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":"https://doi.org/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":"","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":"","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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Asn674Ile mutation in carbamoyl phosphate synthetase 1 promotes enzyme alteration and hyperammonemia in mice. 磷酸氨甲酰合成酶1 Asn674Ile突变促进酶改变和小鼠高氨血症。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-05-27 DOI: 10.1242/dmm.052303

Stuti Bakshi, Taryn Diep, Brandon J Willis, Rachel Reyes, Grace F Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A Cromie, Aimée M Dudley, Johannes Häberle, Gerald S Lipshutz

{"title":"Asn674Ile mutation in carbamoyl phosphate synthetase 1 promotes enzyme alteration and hyperammonemia in mice.","authors":"Stuti Bakshi, Taryn Diep, Brandon J Willis, Rachel Reyes, Grace F Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A Cromie, Aimée M Dudley, Johannes Häberle, Gerald S Lipshutz","doi":"10.1242/dmm.052303","DOIUrl":"https://doi.org/10.1242/dmm.052303","url":null,"abstract":"Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare metabolic disorder that in neonatal onset is typically characterized with severe life-threatening and neurologically injuring hyperammonemic episodes with high unmet patient need. Patients that retain limited enzyme activity may present later in life with less severe hyperammonemia. CPS1 drives the first step in the urea cycle, the pathway terrestrial mammals utilize to metabolize nitrogen. In order to probe the effect of hyperammonemia on the developing nervous system and explore new therapies, a murine Cps1 exon 3-4 mutant was previously generated. However, these mice die within 24 hours of birth, limiting study capabilities. Herein, we developed a novel Cps1 hypomorphic murine model with residual enzyme activity that maintains survival, but with reduction that dysfunction of Cps1 could be detected biochemically. Characterization, based on the orthologous human mutation Asn674Ile, revealed that it is reproducible, 100% penetrant, and biochemically phenocopies the human disorder. The hypomorph presents with elevated ammonia and glutamate and reduced citrulline, and with an impaired rate of ureagenesis, providing a novel platform to study and develop therapies for CPS1 deficiency.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149565","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

frizzled5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma. Frizzled5突变斑马鱼在基因上对小眼症和结肠瘤敏感。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2025-05-22 DOI: 10.1242/dmm.052284

Clinton Monfries, Stephen Carter, Paris Ataliotis, Aya Bseisu, Mahum Shaikh, Maria Hernández-Bejarano, Mohammed Fourteia, Mara Ioana Maftei, Rodrigo M Young, Stephen W Wilson, Gaia Gestri, Florencia Cavodeassi

{"title":"frizzled5 mutant zebrafish are genetically sensitised to developing microphthalmia and coloboma.","authors":"Clinton Monfries, Stephen Carter, Paris Ataliotis, Aya Bseisu, Mahum Shaikh, Maria Hernández-Bejarano, Mohammed Fourteia, Mara Ioana Maftei, Rodrigo M Young, Stephen W Wilson, Gaia Gestri, Florencia Cavodeassi","doi":"10.1242/dmm.052284","DOIUrl":"https://doi.org/10.1242/dmm.052284","url":null,"abstract":"Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are amongst the most severe defects associated with paediatric blindness. FZD5 is a Wnt receptor expressed in the developing eye and individuals with mutations in FZD5 exhibit microphthalmia/coloboma supporting a role for this receptor in human eye formation. Here we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles, display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants we further identified aamp as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119168","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