Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
J Virol. 2019 Aug 28;93(18). doi: 10.1128/JVI.00241-19. Print 2019 Sep 15.
Genomic material from many neurotropic RNA viruses (e.g., measles virus [MV], West Nile virus [WNV], Sindbis virus [SV], rabies virus [RV], and influenza A virus [IAV]) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV and, moreover, that immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs after experimental depletion of cells of the adaptive immune response and is associated with a loss of T resident memory (T) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term-infected mice display severe gait and motor problems, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, immune-mediated viral control in the CNS and demonstrate that what were once considered "resolved" RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection. Viral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented here provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of noncytolytic viral control.
许多神经嗜性 RNA 病毒（例如麻疹病毒 [MV]、西尼罗河病毒 [WNV]、辛德毕斯病毒 [SV]、狂犬病病毒 [RV] 和甲型流感病毒 [IAV]）的基因组物质在急性感染消退后很长时间仍可在小鼠脑组织中检测到。这些 RNA 在没有明显中枢神经系统（CNS）疾病的情况下存在，导致人们认为它们是病毒残余物，几乎没有或没有重新激活的潜力。在这里，我们表明 MV RNA 在 MV 挑战后很长时间仍可在允许的小鼠神经元中检测到，而且免疫抑制会导致 RNA 和蛋白质合成反弹，在急性病毒控制后数月引发神经发病机制。实验性耗尽适应性免疫反应细胞后，病毒转录和蛋白质合成会大量重新出现，并且与脑内 T 常驻记忆（T）淋巴细胞的丧失有关。与急性感染期间所见的疾病不同，与失去免疫控制相关的疾病：免疫细胞耗尽、长期感染的小鼠表现出严重的步态和运动问题，而不是免疫缺陷宿主急性感染时发生的消瘦和致命疾病。这些结果阐明了中枢神经系统中非细胞溶解、免疫介导的病毒控制的潜在后果，并表明曾经被认为是“已解决”的 RNA 病毒感染实际上可能导致以后生活中的疾病与急性感染引起的疾病不同。神经元的病毒感染通常不是细胞病变性的；因此，一旦感染的神经元存活下来，并且在明显的病毒控制之后很长时间都可以检测到病毒 RNA。这些 RNA 通常被认为是病毒化石，不太可能导致中枢神经系统（CNS）疾病。使用麻疹病毒（MV）神经元感染的小鼠模型，我们表明 MV RNA 在急性控制后很长时间以及在没有明显疾病的情况下在感染小鼠的中枢神经系统中得以维持。病毒复制受到适应性免疫反应的抑制；当这些免疫细胞被耗尽时，病毒蛋白合成再次出现，导致与急性感染期间观察到的疾病不同的中枢神经系统疾病。本文提供了理解中枢神经系统中持续性 RNA 感染如何被宿主免疫反应控制以及非细胞溶解病毒控制的致病后果的基础。
