Disease Models & Mechanisms最新文献_第4页

UBA1 knockdown dysregulates UBA1-sensitive proteins and impairs muscle function in models of spinal muscular atrophy X-linked 2. 在果蝇和小鼠中，UBA1敲低会失调UBA1敏感蛋白的水平并损害肌肉功能。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-26 DOI: 10.1242/dmm.052935

Michelle Curley, Flavia A Graca, Anna Stephan, Wei Wang, Vishwajeeth R Pagala, Yong-Dong Wang, Anthony A High, Fabio Demontis

{"title":"UBA1 knockdown dysregulates UBA1-sensitive proteins and impairs muscle function in models of spinal muscular atrophy X-linked 2.","authors":"Michelle Curley, Flavia A Graca, Anna Stephan, Wei Wang, Vishwajeeth R Pagala, Yong-Dong Wang, Anthony A High, Fabio Demontis","doi":"10.1242/dmm.052935","DOIUrl":"10.1242/dmm.052935","url":null,"abstract":"UBA1 is the primary ubiquitin-activating enzyme that initiates ubiquitination, which regulates protein function and turnover. Although UBA1 loss is cell lethal, silent mutations that reduce UBA1 mRNA levels cause spinal muscular atrophy X-linked 2 (SMAX2), a disorder marked by skeletal muscle weakness and wasting. However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle. Here, we examined Drosophila and mice with muscle-targeted UBA1 knockdown and found that this intervention reduced protein ubiquitination, muscle function and lifespan. Integrated transcriptomic and proteomic analyses indicated that a limited set of proteins is modulated post-transcriptionally by Uba1 RNA interference (Uba1RNAi), suggesting that these UBA1-sensitive proteins rely on optimal UBA1 levels for degradation (Uba1RNAi-upregulated proteins) and stability (Uba1RNAi-downregulated proteins). Therefore, despite the general function of UBA1 in ubiquitination, UBA1 knockdown alters the levels of relatively few critical proteins, which may contribute to muscle weakness and SMAX2 pathogenesis. Moreover, although SMAX2-linked UBA1 mutations occur ubiquitously, experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390200","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

Placental defects revealed by modelling Prader-Willi syndrome in mice. 小鼠PWS模型所揭示的胎盘缺陷。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-09-01 DOI: 10.1242/dmm.052833

Anna E Webberley, Raquel Boque-Sastre, Lauren Bailey, Cerys Charles, Rachel A Jones, Rosie Bunton-Stasyshyn, Michelle E Stewart, Sara E Wells, David S Chatelet, Stephanie K Robinson, Matthew J Higgs, Rosalind M John, Anthony R Isles

{"title":"Placental defects revealed by modelling Prader-Willi syndrome in mice.","authors":"Anna E Webberley, Raquel Boque-Sastre, Lauren Bailey, Cerys Charles, Rachel A Jones, Rosie Bunton-Stasyshyn, Michelle E Stewart, Sara E Wells, David S Chatelet, Stephanie K Robinson, Matthew J Higgs, Rosalind M John, Anthony R Isles","doi":"10.1242/dmm.052833","DOIUrl":"10.1242/dmm.052833","url":null,"abstract":"The neurodevelopmental disorder Prader-Willi syndrome (PWS) is caused by paternally derived loss of gene expression from the imprinted interval on chromosome 15q11-q13. Recently, it has been suggested that the abnormal feeding-related behaviours characteristic of PWS can, in part, be developmentally programmed in utero via abnormal placental function. Here, we report that several PWS-associated genes were expressed in mouse placenta with three PWS-associated RNA transcripts, i.e. genes Magel2 and Necdin, and the lncRNA Sngh14, colocalised to the Kdr-positive (Kdr+) foetal endothelial cells of the labyrinth zone central to nutrient transport. In a novel PWS mouse model (Large+/-) we found markedly reduced expression of PWS-associated genes in the placenta and an associated ∼25% reduction in Kdr+ foetal endothelial cells. Although this did not directly translate into a significant reduction in foetal growth late in gestation, these data suggest that placental function and nutrient transfer from mother to foetus could be compromised in PWS contributing to later post-natal phenotypes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396318","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

Restoring comparative expertise to improve translation of animal models. 恢复比较专业知识，提高动物模型的翻译。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-26 DOI: 10.1242/dmm.053172

K C Kent Lloyd

{"title":"Restoring comparative expertise to improve translation of animal models.","authors":"K C Kent Lloyd","doi":"10.1242/dmm.053172","DOIUrl":"10.1242/dmm.053172","url":null,"abstract":"Animal models remain indispensable in biomedical research, particularly for discovering disease mechanisms within intact living organisms. Yet confidence in their human translational relevance has been weakened by apparent failures of preclinical findings to predict clinical outcomes. Although often attributed to species differences, such failures also reflect correctable problems in model selection, experimental design, endpoint choice and phenotype interpretation. A key, but overlooked, contributor is the erosion of comparative expertise in pathobiology and clinical medicine needed to relate animal phenotypes to human disease across species, strain, and developmental, physiological and pathological contexts. This expertise gap can lead investigators to mismatch models to biological questions, misinterpret background abnormalities as engineered phenotypes or extend mechanism-focused models beyond the questions they are suited to answer. New approach methodologies (NAMs), such as in vitro and in silico models, provide important complementary tools, but do not eliminate the need for whole-organism models or resolve this interpretive problem. Ensuring the reliability of biomedical research will require preserving well-justified animal models where whole-organism systems biology remains necessary, integrating validated NAMs only where they are fit for purpose, and rebuilding the comparative expertise needed to interpret both model types rigorously.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 8","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817841","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

RAS-PI3Kα signaling regulates KrasG12D-induced lymphangiogenesis in complex lymphatic anomalies. RAS与PI3Kα的结合调节发育和krasg12d诱导的淋巴管生成。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-27 DOI: 10.1242/dmm.052932

Lorenzo M Fernandes, Jeffrey Tresemer, Angelica Vallejo, Alice Yao, Joshua P Scallan, Michael T Dellinger

{"title":"RAS-PI3Kα signaling regulates KrasG12D-induced lymphangiogenesis in complex lymphatic anomalies.","authors":"Lorenzo M Fernandes, Jeffrey Tresemer, Angelica Vallejo, Alice Yao, Joshua P Scallan, Michael T Dellinger","doi":"10.1242/dmm.052932","DOIUrl":"10.1242/dmm.052932","url":null,"abstract":"Complex lymphatic anomalies (CLAs) are rare diseases characterized by the abnormal development of lymphatic vessels. CLAs can be caused by somatic activating variants in KRAS (e.g. KRASG12D), which stimulate MAPK and PI3K signaling. Although KRAS-MAPK signaling is known to play a critical role in CLA pathogenesis, the contribution of KRAS-PI3Kα signaling remains unclear. To investigate the role of RAS activation of PI3Kα in CLAs, we analyzed mice carrying two missense mutations in the RAS-binding domain of p110α (encoded by Pik3ca), the catalytic subunit of PI3Kα. These two mutations block the interaction between p110α and RAS but do not affect its kinase activity. Disruption of RAS-mediated PI3Kα activation in lymphatic endothelial cells reduced lymphatic vessel branching but did not affect lymphatic valve formation. In KrasG12D-mutant mice, blocking RAS activation of p110α reduced the pathological enlargement of lymphatic vessels, but failed to prevent KrasG12D-induced lymphatic valve loss. Similar results were observed following p110α deletion in KrasG12D-mutant mice. Together, these findings demonstrate that KrasG12D drives distinct disease phenotypes through separate downstream pathways. KRAS-PI3Kα signaling promotes pathological lymphatic vessel enlargement, whereas KRAS-MAPK signaling disrupts lymphatic valve formation.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618846","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

Gut-derived Unpaired-3 cytokine signaling promotes systemic hypoxia tolerance in Drosophila. 肠道来源的Unpaired-3细胞因子信号传导促进果蝇的全身缺氧耐受性。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-09-01 DOI: 10.1242/dmm.052999

Kate Ding, Prajakta Bodkhe, Byoungchun Lee, W Aline Ingelson-Filpula, Danielle Polan, Amy Wycislik, Tiffany Cheung, Sophie Wu, Reeha Rahim, Savraj S Grewal

{"title":"Gut-derived Unpaired-3 cytokine signaling promotes systemic hypoxia tolerance in Drosophila.","authors":"Kate Ding, Prajakta Bodkhe, Byoungchun Lee, W Aline Ingelson-Filpula, Danielle Polan, Amy Wycislik, Tiffany Cheung, Sophie Wu, Reeha Rahim, Savraj S Grewal","doi":"10.1242/dmm.052999","DOIUrl":"10.1242/dmm.052999","url":null,"abstract":"Systemic hypoxia - a reduction in oxygen supply to all tissues and organs - occurs in many physiological and pathological conditions, including fetal development, high-altitude exposure, and disorders such as sleep apnea and respiratory disease. Under these conditions, whole-body physiology must adapt to ensure proper tissue functioning and survival. Although extensive research has characterized how individual cells sense and adapt to low-oxygen conditions, the mechanisms that coordinate whole-body responses to systemic hypoxia remain poorly understood. In this study, we uncovered an inter-organ signaling response mediated by the cytokine Unpaired-3 (Upd3), a functional homolog of human interleukin-6 (IL-6), that is important for systemic hypoxia tolerance in Drosophila. We demonstrated that hypoxia rapidly induces Upd3 expression and activates JAK/STAT signaling in larvae and adults. Interestingly, we discovered a sex-specific requirement for this pathway, with females, but not males, requiring Upd3 for hypoxia survival. We also identified the intestine as a critical source of hypoxia-induced Upd3 and showed that gut-derived Upd3 signals to the fat body and oenocytes to mediate hypoxia tolerance by promoting expression of nitric oxide synthase, the FGF ligand Branchless and the kinase Hipk. Furthermore, we revealed an unexpected role for the canonical hypoxia response transcription factor HIF-1α/Sima as a molecular brake, which prevents lethal Upd3 overproduction, revealing that hypoxia survival requires precise cytokine dosage control. Our findings define a gut-to-fat body signaling axis that coordinates systemic hypoxia adaptation, highlighting cytokine-mediated inter-organ communication as a mechanism for whole-body adaptation to low oxygen, with potential relevance to hypoxia-related human pathologies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469587","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

Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling. HSPB1的Charcot-Marie-Tooth突变逐渐改变秀丽隐杆线虫的神经肌肉信号。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-28 DOI: 10.1242/dmm.052805

Iman Aolymat, Jeff W Barclay

{"title":"Charcot-Marie-Tooth disease variants of HSPB1 progressively alter neuromuscular signalling.","authors":"Iman Aolymat, Jeff W Barclay","doi":"10.1242/dmm.052805","DOIUrl":"10.1242/dmm.052805","url":null,"abstract":"Autosomal dominant variants in HSPB1 can cause type 2 Charcot-Marie-Tooth disease, a progressive neuromuscular disorder. HSPB1 is a small, ATP-independent chaperone that functions in protein folding, stabilisation and stress protection, as well as regulating intracellular processes such as organization of the cytoskeleton. How diverse variants in HSPB1 exert progressive neuromuscular defects is unclear. Using a transgenic Caenorhabditis elegans model, we examined three distinct HSPB1 variants and determined that mutant HSPB1 caused an early defect in neuromuscular signalling strength as assayed by aldicarb sensitivity. Our data point to the effects being presynaptic in origin and unrelated to differences in expression of mutant HSPB1 compared with that of the wild-type protein. In contrast, the early defect in neuromuscular signalling may be a result of a general loss of small chaperone function. We also identified a progressive effect whereby age-dependent changes to neuromuscular signalling were accelerated in worms expressing mutant HSPB1. These effects were not mirrored by a general loss of small chaperone function; however, wild-type HSPB1 expression strikingly protected against progressive defects seen in controls. These results indicate a possible progressive mechanism for HSPB1-dependent neuromuscular defects.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561190","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

Characterising skull pathologies in the Sost-deficient mouse for preclinical evaluation of sclerosteosis treatments. 表征sost缺乏小鼠的颅骨病理，用于硬化治疗的临床前评估。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-26 DOI: 10.1242/dmm.052839

Timothy J Dreyer, Eleanor Gouldie, Jacob A C Keen, Phil Salmon, Gill Holdsworth, Andrew A Pitsillides, Scott J Roberts

{"title":"Characterising skull pathologies in the Sost-deficient mouse for preclinical evaluation of sclerosteosis treatments.","authors":"Timothy J Dreyer, Eleanor Gouldie, Jacob A C Keen, Phil Salmon, Gill Holdsworth, Andrew A Pitsillides, Scott J Roberts","doi":"10.1242/dmm.052839","DOIUrl":"10.1242/dmm.052839","url":null,"abstract":"Facial paralysis, hearing loss and potentially lethal raised intracranial pressure are primary symptoms of sclerosteosis, an ultra-rare, autosomal recessive high bone mass (HBM) condition that predominantly manifests in skull pathologies. Non-invasive treatment remains an unmet clinical need. Recently, PORCN inhibition has been shown to reduce bone mass in young Sost-deficient (Sost-/-) mice. In this paper, we characterised sclerosteosis skull pathologies at later adult stages using a Sost-/- mouse model, with a view to drug efficacy evaluation. This revealed that male and female 9-month-old Sost-/- mice recapitulate the skull overgrowth and neural impingement of human sclerosteosis. We observed that the foramen magnum was narrowed in Sost-/- mice, and that parietal bone mass and thickness were significantly elevated. Otosclerosis was apparent, and animals exhibited significant hearing loss at age 8-9 months. Further, prominent mandibles highlighted hyperostosis in the jaw. Sexual dimorphism was also evident in the Sost-/- mice, underscoring the importance of including both sexes in HBM studies. This study provides new insight into Sost-/--skull-related pathology and further validates Sost-/- mice as a valuable model for investigating potential treatments for sclerosteosis and other HBM related conditions.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 8","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148825155","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

Transdifferentiated BLaER1 cells as a genetically tractable model to study the interaction of pathogenic fungi with macrophages. 转分化BLaER1细胞作为研究病原真菌与巨噬细胞相互作用的遗传可处理模型。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-08-05 DOI: 10.1242/dmm.052865

Johannes Sonnberger, Erik Böhm, Janik Adriana Tomás-Morales, Theresa Lange, Katrin Bagola, Lisa Denner, Lydia Kasper, Sascha Brunke, Ger van Zandbergen, Jakob L Sprague, Bernhard Hube

{"title":"Transdifferentiated BLaER1 cells as a genetically tractable model to study the interaction of pathogenic fungi with macrophages.","authors":"Johannes Sonnberger, Erik Böhm, Janik Adriana Tomás-Morales, Theresa Lange, Katrin Bagola, Lisa Denner, Lydia Kasper, Sascha Brunke, Ger van Zandbergen, Jakob L Sprague, Bernhard Hube","doi":"10.1242/dmm.052865","DOIUrl":"10.1242/dmm.052865","url":null,"abstract":"Macrophages are essential in the defense against fungal disease. Elucidating antimicrobial mechanisms of macrophages and pathogen activities to evade these phagocytes will help in understanding fungal infections. Existing experimental models, however, have a number of disadvantages. Human macrophage-like cell lines offer genetic tractability, but often display reduced antifungal activity and altered phenotypes compared to primary cells. In contrast, primary human monocyte-derived macrophages closely reflect physiological responses but their use is constrained by donor variability, limited availability and restricted genetic manipulability. Here, we establish transdifferentiated BLaER1 cells as a human-derived, highly potent and genetically tractable infection model to study fungal-host interactions. We show that BLaER1 cells display macrophage characteristics and rapidly phagocytose cells of the major fungal pathogens Candida albicans, C. glabrata and C. auris. BLaER1 cells form functional phagolysosomes and elicit pro-inflammatory immune responses. Using knockout BLaER1 cells, we demonstrate for the first time in a human macrophage model that the host factor gasdermin D and the fungal peptide toxin candidalysin have distinct roles in triggering pyroptosis and inducing lytic host cell death.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249547","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

Organoids as brain tumour models: bridging the translational gap. 类器官作为脑肿瘤模型：弥合翻译差距。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-09-01 DOI: 10.1242/dmm.052893

Thomas Willott, Silvia Marino

引用次数: 0

Expanding the scope of Mycobacterium abscessus reference strains to improve pulmonary disease modeling. 扩大脓肿分枝杆菌参考菌株范围以改进肺部疾病建模。

IF 3.6 3区医学

Disease Models & Mechanisms Pub Date : 2026-08-01 Epub Date: 2026-09-01 DOI: 10.1242/dmm.052759

Ruth A Howe, Chavis Tabor, Chandra M Panthi, Guoqing Cheng, Binayak Rimal, Evan Chen, Ngan Nguyen, Gyanu Lamichhane

{"title":"Expanding the scope of Mycobacterium abscessus reference strains to improve pulmonary disease modeling.","authors":"Ruth A Howe, Chavis Tabor, Chandra M Panthi, Guoqing Cheng, Binayak Rimal, Evan Chen, Ngan Nguyen, Gyanu Lamichhane","doi":"10.1242/dmm.052759","DOIUrl":"10.1242/dmm.052759","url":null,"abstract":"Mycobacterium abscessus (Mab) pulmonary disease is an emerging clinical challenge, particularly in individuals with immunosuppression or structural lung disease. No US Food and Drug Administration (FDA)-approved therapies exist, and current multidrug regimens are prolonged, toxic and achieve low cure rates, highlighting the need for improved treatments. Progress depends on preclinical models that faithfully recapitulate human disease, for which strain selection is critical. The widely used reference strain, ATCC 19977, was isolated from a non-pulmonary source but became the default owing to early availability. To assess its relevance for modeling pulmonary disease, we compared it with 15 clinical Mab isolates from lung infections across the United States. In vitro and in a validated mouse lung infection model, ATCC 19977 differed markedly from clinical isolates, exhibiting rapid systemic dissemination, limited lung granuloma formation and early mortality. In contrast, clinical isolates demonstrated greater pulmonary tropism, reduced dissemination and robust lung pathology. We propose a panel of pulmonary clinical isolates representing major Mab subspecies and phenotypes for lung research. These isolates more accurately recapitulate human disease and are expected to enhance the translational relevance of mechanistic and therapeutic studies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"19 8","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864002","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