Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs.
Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs.
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DOI：
10.1371/journal.pntd.0004023
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发表时间：
2015
影响因子：
3.8
通讯作者：
Fu ZF
中科院分区：
文献类型：
--
作者：
Gnanadurai CW;Yang Y;Huang Y;Li Z;Leyson CM;Cooper TL;Platt SR;Harvey SB;Hooper DC;Faber M;Fu ZF
狂犬病病毒（RABV）在人类和动物中引起脑脊髓炎。狂犬病的主要问题之一是感染者通常不会产生病毒中和抗体（VNA）。在这项研究中，我们研究了宿主对犬RABV感染的免疫反应，使用从狂犬病犬中分离的减毒活（TriGAS）或野生型（wt）（DRV-NG 11）RABV。用TriGAS感染狗的实验诱导了血清中高水平的VNA，而野生型RABV感染则没有。感染TriGAS的狗产生了针对病毒（包括其糖蛋白）的抗体，而感染DRV-NG 11的狗仅产生了狂犬病抗体，这些抗体可能对核蛋白（N）而不是糖蛋白（G）具有特异性。我们表明，感染TriGAS诱导引流淋巴结中B细胞的早期活化和血液中DC和B细胞的持续活化。另一方面，用DRV-NG 11感染不能诱导DC和B细胞的活化，并进一步减少CD 4 T细胞的产生。此外，我们表明，鞘内（IT）免疫的TriGAS不仅诱导高水平的VNA在血清中，而且在CSF中，而肌肉内（IM）免疫的TriGAS诱导VNA仅在血清中。此外，在IT免疫的狗的CSF中检测到高水平的总蛋白和WBC，表明血脑屏障（BBB）通透性的瞬时增强，这与免疫效应物从外周进入CNS有关。用TriGAS IM感染狗诱导血清VNA的产生，而在狗中IT免疫TriGAS诱导外周以及CSF中高水平的VNA，并瞬时增强BBB通透性。相反，感染野生型DRV-NG 11导致产生RABV反应性抗体，但VNA和G特异性抗体不存在。结果，所有感染wt DRV-NG 11的狗都死于狂犬病。因此，不能激活保护性免疫是犬RABV发病机制的重要特征之一。狂犬病发病机制的研究已取得显著进展。狂犬病感染的特征之一是人类患者不会发展VNA。在本研究中，研究了犬感染高度减毒RABV（TriGAS）或高致病性真正野生型RABV（DRV-NG 11）后的免疫应答。DRV-NG 11是从狂犬病犬的大脑中分离出来的，尚未在实验室动物或细胞培养中传代。IM感染TriGAS的狗诱导血液中DC和B细胞的早期活化，以及外周中VNA的产生，而IT感染TriGAS不仅在血清中而且在CSF中诱导高水平的VNA。相反，用DRV-NG 11感染狗未能引起VNA。结果，感染wt DRV-NG 11的狗无一存活。DRV-NG 11复制和传播而不触发对糖蛋白的免疫应答的能力显然是其致病性的重要方面。
Rabies virus (RABV) induces encephalomyelitis in humans and animals. One of the major problems with rabies is that the infected individuals most often do not develop virus neutralizing antibodies (VNA). In this study we have investigated the host immune response to RABV infection in dogs, using a live-attenuated (TriGAS) or a wild-type (wt) (DRV-NG11) RABV isolated from a rabid dog. The experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS. IM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs. Remarkable advances have been made in elucidating the pathogenesis of rabies. One of the hallmarks of rabies infection is that human patients do not develop VNA. In this present study, immune responses were investigated in dogs after infection with a highly attenuated RABV (TriGAS) or a highly pathogenic, truly wt RABV (DRV-NG11). DRV-NG11 was isolated from the brain of a rabid dog and has not been passaged in laboratory animals or in cell culture. IM infection of dogs with TriGAS induced early activation of DCs and B cells in the blood, and production of VNA in the periphery, whereas, IT infection with TriGAS induced a high level of VNA not only in the serum but also in the CSF. On the contrary, infection of dogs with DRV-NG11 failed to elicit VNA. As a result, none of the dogs infected with wt DRV-NG11 survived. The ability of DRV-NG11 to replicate and spread without triggering an immune response to glycoprotein is evidently an important facet of its pathogenicity.