BK Polyomavirus Infection of Bladder Microvascular Endothelial Cells Leads to the Activation of the cGAS-STING Pathway

IF 6.8 3区 医学 Q1 VIROLOGY
Kateřina Bruštíková, Boris Ryabchenko, David Liebl, Lenka Horníková, Jitka Forstová, Sandra Huérfano
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Abstract

BK polyomavirus (BKPyV) infection in humans is usually asymptomatic but ultimately results in viral persistence. In immunocompromised hosts, virus reactivation can lead to nephropathy or hemorrhagic cystitis. The urinary tract serves as a silent reservoir for the virus. Recently, it has been demonstrated that human bladder microvascular endothelial cells (HBMVECs) serve as viral reservoirs, given their unique response to infection, which involves interferon (IFN) production. The aim of the present study was to better understand the life cycle of BKPyV in HBMVECs, uncover the molecular pathway leading to IFN production, and to identify the connection between the viral life cycle and the activation of the IFN response. Here, in the early stage of infection, BKPyV virions were found in internalized monopinocytic vesicles, while later they were detected in late endosomes, lysosomes, tubuloreticular structures, and vacuole-like vesicles. The production of viral progeny in these cells started at 36 h postinfection. Increased cell membrane permeability and peaks of virion release coincided with the leakage of viral and cellular DNA into the cytosol at approximately 60 h postinfection. Leaked DNA colocalized with and activated cGAS, leading to the activation of STING and the consequent transcription of IFNB and IFN-related genes; in contrast, the IFN response was attenuated by exposure to the cGAS inhibitor, G140. These findings highlight the importance of the cGAS-STING pathway in the innate immune response of HBMVECs to BKPyV.

Abstract Image

BK 多瘤病毒感染膀胱微血管内皮细胞导致 cGAS-STING 通路激活
人类感染 BK 多瘤病毒(BKPyV)后通常没有症状,但最终会导致病毒持续存在。在免疫力低下的宿主中,病毒再活化可导致肾病或出血性膀胱炎。泌尿道是病毒的无声贮藏库。最近有研究表明,人膀胱微血管内皮细胞(HBMVECs)可作为病毒库,因为它们对感染的独特反应包括产生干扰素(IFN)。本研究旨在更好地了解 BKPyV 在 HBMVECs 中的生命周期,揭示导致 IFN 产生的分子途径,并确定病毒生命周期与 IFN 反应激活之间的联系。研究发现,在感染初期,BKPyV病毒被发现存在于内化的单核细胞囊泡中,而随后则在晚期内体、溶酶体、管状结构和空泡样囊泡中被检测到。这些细胞在感染后 36 小时开始产生病毒后代。感染后约 60 小时,细胞膜通透性增加,病毒释放达到高峰,同时病毒和细胞 DNA 泄漏到细胞膜中。泄漏的DNA与cGAS共定位并激活了cGAS,导致STING被激活,IFNB和IFN相关基因随之转录;相反,暴露于cGAS抑制剂G140会减弱IFN反应。这些发现凸显了 cGAS-STING 通路在 HBMVECs 对 BKPyV 的先天免疫反应中的重要性。
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来源期刊
Journal of Medical Virology
Journal of Medical Virology 医学-病毒学
CiteScore
23.20
自引率
2.40%
发文量
777
审稿时长
1 months
期刊介绍: The Journal of Medical Virology focuses on publishing original scientific papers on both basic and applied research related to viruses that affect humans. The journal publishes reports covering a wide range of topics, including the characterization, diagnosis, epidemiology, immunology, and pathogenesis of human virus infections. It also includes studies on virus morphology, genetics, replication, and interactions with host cells. The intended readership of the journal includes virologists, microbiologists, immunologists, infectious disease specialists, diagnostic laboratory technologists, epidemiologists, hematologists, and cell biologists. The Journal of Medical Virology is indexed and abstracted in various databases, including Abstracts in Anthropology (Sage), CABI, AgBiotech News & Information, National Agricultural Library, Biological Abstracts, Embase, Global Health, Web of Science, Veterinary Bulletin, and others.
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