先天免疫不会损害丁型肝炎病毒感染，但会增加细胞毒性 T

StephenW

先天免疫不会损害丁型肝炎病毒感染，但会增加细胞毒性 T 细胞的活性
Sebastian Maximilian Altstetter 1 , Oliver Quitt 1 , Francesca Pinci 2 , Veit Hornung 2 , Aaron Michael Lucko 1 , Karin Wisskirchen 1 , Stephanie Jung 1 3 , Ulrike Protzer 1 4
隶属关系
隶属关系

    1
    慕尼黑亥姆霍兹中心医学院病毒学研究所/慕尼黑工业大学，德国慕尼黑 81675。
    2
    德国慕尼黑路德维希马克西米利安大学基因中心和生物化学系，81377。
    3
    心血管免疫学研究所，波恩大学医院，波恩大学，53127 波恩，德国。
    4
    德国感染研究中心 (DZIF)，慕尼黑合作伙伴站点，81675 慕尼黑，德国。

    PMID：34831475 DOI：10.3390/cells10113253

抽象的

全世界大约有 7000 万人受到慢性丁型肝炎的影响，由于慢性炎症，慢性丁型肝炎会迅速导致肝硬化和肝细胞癌。这种由丁型肝炎病毒 (HDV) 和乙型肝炎病毒 (HBV) 共同感染引起的慢性炎症的触发因素和后果知之甚少。使用 CRISPR 技术，我们表征了细胞内先天免疫对 HDV 单一感染和合并感染的识别，并使用不同的 HBV 和 HDV 许可肝癌细胞系确定了其对病毒生命周期和效应 T 细胞反应的影响。我们表明，MDA5 检测到 HDV 感染，并且 - 在滞后期之后 - 在受感染的细胞中诱导深刻的 I 型干扰素反应。然而，I 型干扰素反应无法抑制 HDV 复制或传播，因此提供了持续触发。使用针对 HBV 和 HDV 常用的包膜蛋白的工程化 T 细胞，我们发现 HDV 免疫识别增强了 T 细胞的细胞毒性。有趣的是，T 细胞效应器功能的增强与抗原呈递无关。这些发现有助于解释慢性丁型肝炎患者中免疫介导的组织损伤，并表明将先天性触发因素与 T 细胞激活疗法相结合可能是一种治愈方法。

关键词：MDA5； T 细胞依赖性细胞毒性； T细胞工程；抗病毒反应；乙型肝炎病毒;丁型肝炎病毒；先天免疫。
拨款支持

    TRR179/Deutsche Forschungsgemeinschaft
    PD-318/Helmholtz-Gemeinschaft, Impuls- 和 Vernetzungsfonds
    TRR338/Deutsche Forschungsgemeinschaft

StephenW

Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity
Sebastian Maximilian Altstetter  1 , Oliver Quitt  1 , Francesca Pinci  2 , Veit Hornung  2 , Aaron Michael Lucko  1 , Karin Wisskirchen  1 , Stephanie Jung  1   3 , Ulrike Protzer  1   4
Affiliations
Affiliations

    1
    Institute of Virology, School of Medicine, Helmholtz Zentrum München/Technical University of Munich, 81675 Munich, Germany.
    2
    Gene Center and Department of Biochemistry, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
    3
    Institute of Cardiovascular Immunology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
    4
    German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany.

    PMID: 34831475 DOI: 10.3390/cells10113253

Abstract

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach.

Keywords: MDA5; T-cell dependent cytotoxicity; T-cell engineering; antiviral response; hepatitis B virus; hepatitis delta virus; innate immunity.
Grant support

    TRR179/Deutsche Forschungsgemeinschaft
    PD-318/Helmholtz-Gemeinschaft, Impuls- und Vernetzungsfonds
    TRR338/Deutsche Forschungsgemeinschaft