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Expanding virus susceptibility spectrum of MDBK cells by expressing host receptors nectin 4 and TfR.

ABSTRACT: Cell-based vaccine manufacturing is a flexible and cost-effective approach for vaccine production which, however, requires cell adaptation to new vaccine strains. Generating one omnipotent or semi-omnipotent cell line feasible for the production of multiple viruses could help resolve this problem. We previously proposed virus Baltimore subtyping-based choice of receptors and a panel of minimally preferred receptors for the establishment of cells with a broad virus susceptibility spectrum. With the aim of establishing cells sensitive to viruses of livestocks including bovine, ovine and canine, we selected TfR and Nectin 4 from the minimally preferred receptor panel, and successfully sensitized the starting cell line MDBK to CPV and CDV infection. Our study is a preliminary validation of our previously identified associations between host receptor usage and virus Baltimore subtyping. Evidence from more viruses of the same Baltimore subtyping and more starting cell lines need to be used to consolidate our results.

SUBMITTER: Han P

PROVIDER: S-EPMC7832251 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Expanding virus susceptibility spectrum of MDBK cells by expressing host receptors nectin 4 and TfR.

Han Peiyu P Zhang Xuanhao X Yang Siming S Dai Xiaofeng X Lv Qing Q Hua Dong D

Journal of virological methods 20201207

Cell-based vaccine manufacturing is a flexible and cost-effective approach for vaccine production which, however, requires cell adaptation to new vaccine strains. Generating one omnipotent or semi-omnipotent cell line feasible for the production of multiple viruses could help resolve this problem. We previously proposed virus Baltimore subtyping-based choice of receptors and a panel of minimally preferred receptors for the establishment of cells with a broad virus susceptibility spectrum. With t ...[more]

PMID: 33301791

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Project description:Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV's ability to enter murine hepatocytes in vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C. IMPORTANCE:At least 150 million individuals are chronically infected with HCV and are at risk of developing serious liver disease. Despite the advent of effective antiviral therapy, the frequency of chronic carriers has only marginally decreased. A major roadblock in developing a vaccine that would prevent transmission is the scarcity of animal models that are susceptible to HCV infection. It is poorly understood why HCV infects only humans and chimpanzees. To develop an animal model for hepatitis C, previous efforts focused on modifying the host environment of mice, for example, to render them more susceptible to HCV infection. Here, we attempted a complementary approach in which a laboratory-derived HCV variant was tested for its ability to infect mice. We demonstrate that this engineered HCV strain can enter mouse liver cells but does not replicate efficiently. Thus, additional adaptations are likely needed to construct a robust animal model for HCV.

Dataset Information

Expanding virus susceptibility spectrum of MDBK cells by expressing host receptors nectin 4 and TfR.

Publications

Expanding virus susceptibility spectrum of MDBK cells by expressing host receptors nectin 4 and TfR.

Similar Datasets

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