Disease models & mechanisms
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The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and >22 million people infected and >775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans leading to coronavirus disease 2019 (COVID-19). The development of effective clinical interventions, such as antivirals and vaccines that can limit or even prevent the burden and spread of SARS-CoV-2, is a global health priority. ⋯ In this Special Article, we discuss the cell-based and animal models of SARS-CoV-2 infection and pathogenesis that have been described as of August 2020. We also outline the outstanding questions for which researchers can leverage animal and cell-based models to improve our understanding of SARS-CoV-2 pathogenesis and protective immunity. Taken together, the refinement of models of SARS-CoV-2 infection will be critical to guide the development of therapeutics and vaccines against SARS-CoV-2 to end the COVID-19 pandemic.
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Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. ⋯ LOXL1 activity might drive collagen remodelling in IPF lungs. The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs. Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF.
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Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. ⋯ With the recent emergence of tools for altering the rat genome, notably genome-editing technologies, the technological gap between the two organisms is closing, and it is becoming more important to consider the physiological, anatomical, biochemical and pharmacological differences between rats and mice when choosing the right model system for a specific biological question. The aim of this short review and accompanying poster is to highlight some of the most important differences, and to discuss their impact on studies of human diseases, with a special focus on neuropsychiatric disorders.
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In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). ⋯ The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung disease, in order to fully describe and understand dynamic processes during lung disease onset, progression and therapy. This is highly relevant for the translation of therapy evaluation results from preclinical studies to human patients.
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Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. ⋯ Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.