免疫抑制促进BK病毒感染致病性机制与逆转策略研究

BK polyomavirus (BKV) infection in kidney transplant recipients can lead to BKV associated nephropathy (BKVAN) and hemorrhagic cystitis (HC). Due to the absence of effective antiviral treatment, such infections seriously threaten kidney allograft survival. We have found that infection of BKV in renal epithelial cells deficient of IFNα/β receptor or treated with immunosuppression drug could trigger lytic cell death with membrane disruption and release of inflammatory cytokines. Hence, we hypothesize that under immunocompromised conditions, BKV infection can switch from persistent to pathogenic, resulting in the release of virus progeny and inflammatory cytokines which lead to BKV reactivation (Viruria and Viremia) and inflammatory diseases (BKVAN and HC). By adopting the immunosuppression-promoted BKV pathogenic infection models, we aim to identify the manner of cell death induced by lytic BKV infection and the key molecule(s) involved, which would provide the potential targets for reversal strategy development. Results from this study will eventually enrich our knowledge on the hidden mechanisms of pathogenic BKV infection and shed light on its prophylaxis and treatment.

BK病毒（BKV）在肾移植受者中能引起BKV相关肾病和出血性膀胱炎，严重威胁移植肾存活，但临床上缺乏有效的抗病毒手段。本课题组发现，在阻断天然免疫抗病毒通路或在处理免疫抑制剂时，BKV感染肾小管上皮细胞激活裂解性细胞死亡通路，导致细胞膜破裂和炎症因子的释放。因此我们推测：当免疫力受损时，BKV从持续性感染转向致病性感染，裂解细胞释放大量的子病毒和炎症因子，临床表现为BKV的活化（病毒尿症和病毒血症）和BKV相关炎症性疾病（BKV相关肾病和出血性膀胱炎）。本研究将利用免疫抑制下BKV感染的疾病模型，从体外、体内和临床样本水平上研究BKV裂解性感染引起的肾小管上皮细胞死亡方式、关键信号分子以及靶向它们的逆转策略。本研究的成果将丰富我们对BKV致病机理的认识，指导对BKV相关疾病的防治。

BK多瘤病毒（BK polyomavirus，BKV）是一种机会性病毒，人群携带率超过85%。BKV在免疫低下人群容易发生活化，引起病毒尿症、病毒血症和BKV相关性疾病。本研究前期发现BKV在多种细胞中引起裂解性感染，可能有利于其释放子代病毒扩大感染。对此进行研究有望解析BKV裂解性感染及其致病机制，探索靶向性治疗方案。为此，本研究在RPTEC、TCCSUP及HK2等细胞中建立了BKV裂解性感染模型，明确了BKV诱导Caspase3活化进而激活下游GSDME焦亡通路和PARP凋亡通路的分子机制，发现这一作用可能与BKV早期表达基因LT密切相关。通过IFNβ处理或靶向I型干扰素受体通路有望抑制BKV裂解性感染。本研究结果可以为BKV的临床诊断及治疗策略提供一定的理论基础。