The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system.
The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system.
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DOI：
10.1371/journal.pntd.0000535
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发表时间：
2009-10-06
影响因子：
3.8
通讯作者：
Roy A
中科院分区：
文献类型：
--
作者：
Hooper DC;Phares TW;Fabis MJ;Roy A
狂犬病的发病机制与免疫效应物无法通过血脑屏障传递和无法清除中枢神经系统组织中的狂犬病病毒有关。然而，促进免疫效应物进入中枢神经系统组织的机制是由减毒狂犬病病毒感染诱导的。用减毒的狂犬病毒感染正常小鼠，而不接种灭活的狂犬病毒，可促进致病性狂犬病毒从中枢神经系统清除。B细胞缺陷小鼠的T细胞活性可以控制CNS中减毒病毒的复制，但病毒mRNA持续存在。低水平的被动给药狂犬病病毒中和抗体到达B细胞缺陷小鼠小脑中的感染细胞，但不足以介导病毒清除。这一过程需要B细胞侵入中枢神经系统组织产生狂犬病毒特异性抗体，并且在感染减毒狂犬病毒的小鼠中枢神经系统中积累的B细胞中有相当大比例产生病毒特异性抗体。免疫效应物进入狂犬病毒感染组织所需的机制是由减毒狂犬病毒感染诱导的，而不是由致病性狂犬病毒感染或灭活病毒免疫诱导的。T细胞的活性可以抑制狂犬病毒的复制，但通过浸润B细胞产生狂犬病毒特异性抗体，而不是通过血脑屏障漏出循环抗体，对消除病毒至关重要。这些研究结果提示，在病毒到达中枢神经系统组织后，只要适当的免疫效应物能够靶向感染组织，致病性狂犬病病毒感染是可以治疗的。全世界每年有5万多人死于狂犬病，主要原因是发展中国家狂犬病疫苗供应不足。然而，即使有疫苗，如果没有识别出暴露于致病病毒并且没有及时寻求疫苗接种，也会发生人死于狂犬病的情况。这是因为由自然感染或现有疫苗引起的狂犬病毒免疫通常不能有效地从脑组织中清除引起疾病的狂犬病毒。我们的研究揭示了为什么会出现这种情况，以及如何改变疫苗接种，从而使免疫反应从脑组织中清除病毒。我们表明，狂犬病减毒活疫苗诱导的免疫反应类型可能是关键。在动物模型中，减毒狂犬病病毒活疫苗能够有效地将能够清除病毒的免疫细胞输送到中枢神经系统组织中，并促进已扩散到大脑的狂犬病病毒感染的恢复，而基于灭活狂犬病病毒的传统疫苗则没有。侵入中枢神经系统组织的B细胞产生狂犬病特异性抗体对于完全消除病毒很重要。我们假设，在病毒通过中枢神经系统到达但未广泛传播后被诊断为狂犬病毒的个体，类似的机制可能会促进其清除。
The pathogenesis of rabies is associated with the inability to deliver immune effectors across the blood-brain barrier and to clear virulent rabies virus from CNS tissues. However, the mechanisms that facilitate immune effector entry into CNS tissues are induced by infection with attenuated rabies virus. Infection of normal mice with attenuated rabies virus but not immunization with killed virus can promote the clearance of pathogenic rabies virus from the CNS. T cell activity in B cell–deficient mice can control the replication of attenuated virus in the CNS, but viral mRNA persists. Low levels of passively administered rabies virus–neutralizing antibody reach infected cells in the cerebellum of B cell–deficient mice but are not sufficient to mediate virus clearance. Production of rabies virus-specific antibody by B cells invading CNS tissues is required for this process, and a substantial proportion of the B cells that accumulate in the CNS of mice infected with attenuated rabies virus produce virus-specific antibodies. The mechanisms required for immune effectors to enter rabies virus-infected tissues are induced by infection with attenuated rabies virus but not by infection with pathogenic rabies viruses or immunization with killed virus. T cell activities can inhibit rabies virus replication, but the production of rabies virus–specific antibodies by infiltrating B cells, as opposed to the leakage of circulating antibody across the BBB, is critical to elimination of the virus. These findings suggest that a pathogenic rabies virus infection may be treatable after the virus has reached the CNS tissues, providing that the appropriate immune effectors can be targeted to the infected tissues. Every year over 50,000 people die from rabies worldwide, primarily due to the poor availability of rabies vaccine in developing countries. However, even when vaccines are available, human deaths from rabies occur if exposure to the causative virus is not recognized and vaccination is not sought in time. This is because rabies virus immunity induced by the natural infection or current vaccines is generally not effective at removing disease-causing rabies virus from brain tissues. Our studies provide insight into why this is the case and how vaccination can be changed so that the immune response can clear the virus from brain tissues. We show that the type of immune response induced by a live-attenuated rabies virus vaccine may be the key. In animal models, live-attenuated rabies virus vaccines are effective at delivering the immune cells capable of clearing the virus into CNS tissues and promote recovery from a rabies virus infection that has spread to the brain while conventional vaccines based on killed rabies virus do not. The production of rabies-specific antibody by B cells that invade the CNS tissues is important for complete elimination of the virus. We hypothesize that similar mechanisms may promote rabies virus clearance from individuals who are diagnosed after the virus has reached, but not extensively spread, through the CNS.
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影响因子：
4.4
作者：
Phares, Timothy W.;Fabis, Marzena J.;Hooper, D. Craig
通讯作者：
Hooper, D. Craig
影响因子：
4.4
作者：
Tschen, SI;Bergmann, CC;Stohlman, SA
通讯作者：
Stohlman, SA
影响因子：
3.2
作者：
Roy, Anirban;Hooper, D. Craig
通讯作者：
Hooper, D. Craig
影响因子：
5.4
作者：
Roy, Anirban;Hooper, D. Craig
通讯作者：
Hooper, D. Craig
DOI：
10.1073/pnas.89.15.7252
发表时间：
1992-08-01
影响因子：
11.1
作者：
DIETZSCHOLD, B;KAO, M;KOPROWSKI, H
通讯作者：
KOPROWSKI, H