Table_2_Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks.docx

The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3–4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.

小激动剂化合物激活模式识别受体（PRRs），包括TLR样和RIG-I受体，其抗病毒特性已在临床前研究中得到评估，并正在临床试验中针对慢性乙型肝炎（CHB）进行测试。其他PRRs在调节乙型肝炎病毒感染中的作用尚不明确。因此，感染木瓜肝炎病毒（WHV）后急性乙型肝炎（AHB）得到缓解的木瓜，根据其病毒血症和抗原血症的动力学变化，被定义为正常或延迟缓解的动物，并对其存在及表达的各种PRRs进行了检测。尽管感染后立即PRR表达未发生变化，但在肝脏缓解阶段，大多数受体表达显著上调，而在血液中则没有观察到。除了已知的PRRs，如TLR7/8/9和RIG-I外，其他尚未充分表征的受体，如IFI16、ZBP1/DAI、AIM2和NLRP3，也表现出相似甚至更高的表达水平。与正常缓解相比，在延迟缓解期间，受体表达峰值和WHV特异性B细胞和T细胞反应滞后了3-4周。这表明，当WHV复制积累达到一定程度时，木瓜肝脏中的PRR上调发生，并且多个受体参与了随后抗病毒免疫反应的诱导。在正常缓解早期，肝脏酶水平升高，表明细胞溶解机制的诱导速度快于延迟缓解，并且与自然杀伤细胞和CD8标记物以及细胞溶解效应分子的表达增加相关。然而，在延迟缓解期间，尽管肝脏酶水平峰值较低，但肝炎症更为明显，且与细胞溶解标记物的较高表达相关。进一步比较PRR表达发现，在已确立和进展的CHB木瓜中，大多数受体表达显著降低，且RNA传感器比DNA传感器更为明显。这与受体适配器和效应分子表达的降低相关，表明持续的、高水平的WHV复制干扰了PRR的激活，并且与基于免疫细胞标记物表达减少和WHV特异性B细胞和T细胞反应缺失的病毒免疫力下降相关。总的来说，PRRs在缓解和WHV感染持续过程中的不同表达强调了它们在AHB最终病毒控制中的重要性，这种控制能力在CHB期间受到损害。