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Expression data from two rat strains comparing naïve vs 24h picornavirus infection.

ABSTRACT: Allergic (Th2high immunophenotype) asthmatics have a heightened susceptibility to common respiratory viral infections such as human rhinovirus. Evidence suggests that the innate interferon response is deficient in asthmatic/atopic individuals, whilst other studies show no differences in antiviral response pathways. Unsensitized and OVA-sensitized/challenged Th2high (BN rats) and Th2low immunophenotype (PVG rats) animals were inoculated intranasally with attenuated mengovirus (vMC0). Sensitized animals were exposed/unexposed during the acute viral response phase. Cellular and transcriptomic profiling was performed on bronchoalveolar lavage cells. In unsensitized PVG rats, vMC0 elicits a prototypical antiviral response (neutrophilic airways inflammation, upregulation of Th1/type I interferon-related pathways). In contrast, response to infection in the Th2high BN rats was associated with a radically altered intrinsic host response to respiratory viral infection, characterized by macrophage influx/Th2-associated pathways. In sensitized animals, response to virus infection alone was not altered compared to unsensitized animals. However, allergen exposure of sensitized animals during viral infection unleashes a notably exaggerated airways inflammatory response profile orders of magnitude higher in BN versus PVG rats despite similar viral loads. The coexposure responses in the Th2high BN incorporated type I interferon/Th1, alternative macrophage activation/Th2 and Th17 signatures. Similar factors may underlie the hyper-susceptibility to infection-associated airways inflammation characteristic of the human Th2high immunophenotype.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE98152 | GEO | 2018/08/16

REPOSITORIES: GEO

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Project description:To examine the influence cellular and genetics on the procainamide-induced autoimmune response in spleens we compared rats that are genetically Th2-predisposed (Brown Norway), Th1-predisposed (Lewis) or not genetically predisposed (Sprague Dawley). Rats were treated with procainamide three times per week. From the second week, blood samples were taken once a week for antinuclear antibody (ANA) detection. At 56d after treatment, rats were sacrificed and spleens samples were collected for microarray test and histopathology examination. Frequencies of T cell subsets and B cells in rat spleen were measured to assess the effects on splenocyte. Also, 12 serum cytokines/chemokines were determined to explored the Th1/Th2 cytokine pattern after treatment. We found that ANA were makedly elevated in BN and SD rats, while the elevated appeared earlier in BN rats, and the magnitude of its increase were much higher than that of SD rats. There was no marked change in serum ANA in Lewis rats. Histopathological analysis indicated that spleen weight increased significantly both in BN and SD rats after stimulated with procainamide. No significant changes in spleen weight and lesions were observed in Lewis rats. We also found the percentage of CD86 positive cells in spleen of BN rats was significantly increased, while the percentage of CD4+CD25+ cells was decreased in BN rats. In addition, percentage of CD11b/c positive cells were decreased, and the levels of Th-2 (IL-10), Th-1 type cytokine (IFN-γ) and chemokine (IL-1β) in serum were markedly elevated both in BN and SD rats after treatment. Th-2 type cytokine (IL-4, IL-6) in serum were markedly increased only in BN rats. Furthermore, similar immune mechanisms were found in BN and SD rat, and the altered genes were mainly associated in immune response, and inflammatory response. However, the number of differentially expressed genes (DEGs) in BN rats was higher than that in SD rats. Overall, we revealed significant differences in response to autoimmunity induced by procainamide among three strains rats, the BN rats was the most sensitive one, SD rats exhibited less sensitive while Lewis resistance to procainamide. Much more pronounced of Th2-type responses and more complex DEGs involved in immune regulation and response in BN rats might contribute to its susceptible to drug-induced lupus erythematosus. Moreover, similar immune mechanisms were found between BN and SD rat, which suggesting that these changes would served as the potential bridge biomarkers to predict drug-induced autoimmune reactions among species. The results may also provide a scientic basis for the high sensitivity of BN rats in prediction immunotoxicity in preclinical studies.

Project description:We are using ACI and BN rats, which differ markedly in their susceptibility to 17beta-Estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks and cell proliferation, apoptosis, differentiation and gene expression were evaluated. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the extracellular matrix (ECM). Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in part, the differences in mammary cancer susceptibility exhibited by ACI and BN rats. Two groups of 17beta-estradiol treated female rats were compared. Five ACI and five BN rats were treated with 17beta-estradiol for 12 weeks. Total RNA was isolated from the mammary glands of these animals, labeled, and hybridized to Affymetrix Rat Genome 230 2.0 Arrays (Affymetrix Inc.). Significantly differentially expressed genes were found between these groups.

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Expression data from two rat strains comparing naïve vs 24h picornavirus infection.

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