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Precision mouse models with expanded tropism for human pathogens.

ABSTRACT: A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.

SUBMITTER: Wahl A

PROVIDER: S-EPMC6776695 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Precision mouse models with expanded tropism for human pathogens.

Wahl Angela A De Chandrav C Abad Fernandez Maria M Lenarcic Erik M EM Xu Yinyan Y Cockrell Adam S AS Cleary Rachel A RA Johnson Claire E CE Schramm Nathaniel J NJ Rank Laura M LM Newsome Isabel G IG Vincent Heather A HA Sanders Wes W Aguilera-Sandoval Christian R CR Boone Allison A Hildebrand William H WH Dayton Paul A PA Baric Ralph S RS Pickles Raymond J RJ Braunstein Miriam M Moorman Nathaniel J NJ Goonetilleke Nilu N Victor Garcia J J

Nature biotechnology 20190826 10

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implan ...[more]

PMID: 31451733

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Project description:BackgroundNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5' untranslated region of the NOTCH2NLC gene was identified as the causative factor. NIID is a heterogeneous disorder with variable clinical manifestations including cognitive impairment, cerebellar ataxia, parkinsonism, paroxysmal symptoms, autonomic dysfunction, and muscle weakness. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain.ResultsIn this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62 (also known as sequestosome 1, SQSTM1)-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients.ConclusionsOur study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities.

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Precision mouse models with expanded tropism for human pathogens.

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Precision mouse models with expanded tropism for human pathogens.

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