Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64660 | GEO | 2015/01/06
SECONDARY ACCESSION(S): PRJNA271585
REPOSITORIES: GEO
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Project description:New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.
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Project description:ObjectiveAnimal studies remain essential for understanding mechanisms of epilepsy and identifying new therapeutic targets. However, existing animal models of epilepsy do not reflect the high level of genetic diversity found in the human population. The Collaborative Cross (CC) population is a genetically diverse recombinant inbred panel of mice. The CC offers large genotypic and phenotypic diversity, inbred strains with stable genomes that allow for repeated phenotypic measurements, and genomic tools including whole genome sequence to identify candidate genes and candidate variants.MethodsWe evaluated multiple complex epileptic traits in a sampling of 35 CC inbred strains using the flurothyl-induced seizure and kindling paradigm. We created an F2 population of 297 mice with extreme seizure susceptibility and performed quantitative trait loci (QTL) mapping to identify genomic regions associated with seizure sensitivity. We used quantitative RNA sequencing from CC hippocampal tissue to identify candidate genes and whole genome sequence to identify genetic variants likely affecting gene expression.ResultsWe identified new mouse models with extreme seizure susceptibility, seizure propagation, epileptogenesis, and SUDEP (sudden unexpected death in epilepsy). We performed QTL mapping and identified one known and seven novel loci associated with seizure sensitivity. We combined whole genome sequencing and hippocampal gene expression to pinpoint biologically plausible candidate genes (eg, Gabra2) and variants associated with seizure sensitivity.SignificanceNew mouse models of epilepsy are needed to better understand the complex genetic architecture of seizures and to identify therapeutics. We performed a phenotypic screen utilizing a novel genetic reference population of CC mice. The data we provide enable the identification of protective/risk genes and novel molecular mechanisms linked to complex seizure traits that are currently challenging to study and treat.
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Project description:To investigate the function T and B cells in SARS-CoV-2 infection, we utilized Rag2-/- mice and infected them with a mouse adapted strain of SARS-CoV-2 virus (MA30) We then performed gene expression analysis using data obtained from RNA-seq of the lungs of 3 Rag2+/+ and 3 Rag2-/- mice at 3 days post-infection (DPI) with MA30.
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Project description:To explore the effects of SARS-CoV-2 proteins on expression of host genes in lung of infected mice, 4 groups of K18-hACE2 mice (4 mice per group) were mock-infected or infected cells with SARS-CoV-2 WT or its NPS1, or NSP15 mutants respectively.The mice were euthanized at 4 days post-infection to collect the lungs to isolate RNA for RNA sequencing.
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Project description:Purpose: To characterize the differential mRNA expression profiles of lung tissues upon PRRSV infection in different pig breeds, using NGS techonology, we sequenced mRNAs of the lungs of Tongcheng and Landrace pigs before (0 dpi) and after (3, 5, 7 dpi) infection with high-pathogenic PRRSV (HP-PRRSV). Methods: The mRNA expression profiles of the lungs of Tongcheng and Landrace pigs before (0 dpi) and after (3, 5, 7 dpi) HP-PRRSV infection were produced by using solexa platform. The raw reads with low qualities were filtered and the clean high quality reads were mapped to Ensembl Sus reference genome 10.2.71 using BOWTIE2. The unique mapped reads were retained for mRNA expression analysis. The raw reads counts of each mRNA were calculated by HTseq and the differentially expressed mRNA (Fold change >2; FDR <0.05) were called using DEGseq.
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Project description:Male WT C57BL/6j mice (stock #000664, age 8-10 wks) and IL-33 knockout (KO) mice (B6 background) were anesthetized via isoflurane, followed by the intranasal infection with mouse adapted SARS-CoV-2 CMA3p20 (5×10^5 PFU). Mock mice were administrated with identical volumes of cell culture medium. Lungs were perfused with cold PBS and were harvested at days 2 and 4 post-infection. Lung RNA was isolated by Qiagen RNeasy Kits, followed by the Poly (A) RNA sequencing. We then performed differential expression analysis, meta-analysis, and gene set enrichment anaylsis using data obtained by RNA-seq of mock, IL-33 KO, and WT SARS-CoV-2-infected mice.
2023-11-13 | GSE247370 | GEO
Project description:The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1−/−), and STAT1 knockout (STAT1−/−) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Ten week old 129S6/SvEv wild-type, STAT1−/− (Taconic Farms, Germantown, NY), and IFNAR1−/− mice bred on a 129SvEv background were anesthetized with a ketamine and infected intranasally with either phosphate-buffered saline (PBS) alone (Invitrogen, Carlsbad, CA) or 1 × 10^5 PFU rMA15-PBS. Mice were euthanized and left lungs were harvested from individual mice (a total of 3 infected mice from each strain) at days 2, 5, and 9 postinfection (dpi) for microarray analyses. Lung samples were taken from mock-infected animals from each of the strains at 5 dpi.
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Project description:We performed transcriptomic profiling of cells derived from human pluripotent stem cells (PSCs) using our previously described distal lung directed differentiation protocol to generate alveolar type II epithelial-like cells (iAT2s). We used the SPC2 human iPSC line containing a SFTPC-tdTomato knock-in reporter. SFTPC-tdTomato+ iAT2s were sorted on day 41 and again on day 69 of differentiation. iAT2s were single-cell passaged in self-renewing 3D alveolosphere culture approximately every 2 weeks through day 194 of differentiation. On day 208, iAT2s were single-cell passaged onto Transwell inserts. Apical media was removed on day 210 to initiate air-liquid interface culture. On day 218, 6 replicate wells of iAT2s were exposed to SARS-CoV-2 in an apical inoculum and 3 replicate wells were exposed to mock. On day 219, three mock and three post-infection samples (1 dpi) were collected. Three additional post-infection samples (4 dpi) were collected on day 222. We find that SARS-CoV-2 infected iAT2s express a rapid global transcriptomic change characterized by a shift to an inflammatory phenotype, time-dependent epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program.
2020-09-21 | GSE153277 | GEO