Hooper D C, Morimoto K, Bette M, Weihe E, Koprowski H, Dietzschold B
Center for Neurovirology, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107-6799, USA.
J Virol. 1998 May;72(5):3711-9. doi: 10.1128/JVI.72.5.3711-3719.1998.
To investigate the involvement of various cellular and humoral aspects of immunity in the clearance of rabies virus from the central nervous system, (CNS), we studied the development of clinical signs and virus clearance from the CNS in knockout mice lacking either B and T cells, CD8+ cytotoxic T cells, B cells, alpha/beta interferon (IFN-alpha/beta) receptors, IFN-gamma receptors, or complement components C3 and C4. Following intranasal infection with the attenuated rabies virus CVS-F3, normal adult mice of different genetic backgrounds developed a transient disease characterized by loss of body weight and appetite depression which peaked at 13 days postinfection (p.i.). While these animals had completely recovered by day 21 p.i., mice lacking either B and T cells or B cells alone developed a progressive disease and succumbed to infection. Mice lacking either CD8+ T cells, IFN receptors, or complement components C3 and C4 showed no significant differences in the development of clinical signs by comparison with intact counterparts having the same genetic background. However, while infectious virus and viral RNA could be detected in normal control mice only until day 8 p.i., in all of the gene knockout mice studied except those lacking C3 and C4, virus infection persisted through day 21 p.i. Analysis of rabies virus-specific antibody production together with histological assessment of brain inflammation in infected animals revealed that clearance of CVS-F3 by 21 days p.i. correlated with both a strong inflammatory response in the CNS early in the infection (day 8 p.i.), and the rapid (day 10 p.i.) production of significant levels of virus-neutralizing antibody (VNA). These studies confirm that rabies VNA is an absolute requirement for clearance of an established rabies virus infection. However, for the latter to occur in a timely fashion, collaboration between VNA and inflammatory mechanisms is necessary.
为了研究免疫的各种细胞和体液方面在狂犬病病毒从中枢神经系统（CNS）清除过程中的作用，我们研究了缺乏B细胞和T细胞、CD8+细胞毒性T细胞、B细胞、α/β干扰素（IFN-α/β）受体、IFN-γ受体或补体成分C3和C4的基因敲除小鼠的临床症状发展以及病毒从中枢神经系统的清除情况。在用减毒狂犬病病毒CVS-F3鼻内感染后，不同遗传背景的正常成年小鼠出现一种短暂性疾病，其特征为体重减轻和食欲减退，在感染后第13天达到峰值。虽然这些动物在感染后第21天已完全恢复，但缺乏B细胞和T细胞或仅缺乏B细胞的小鼠却发展为进行性疾病并死于感染。与具有相同遗传背景的完整对照小鼠相比，缺乏CD8+T细胞、IFN受体或补体成分C3和C4的小鼠在临床症状发展方面没有显著差异。然而，虽然在正常对照小鼠中仅在感染后第8天之前能检测到传染性病毒和病毒RNA，但在除缺乏C3和C4的小鼠之外的所有研究的基因敲除小鼠中，病毒感染一直持续到感染后第21天。对狂犬病病毒特异性抗体产生的分析以及对感染动物脑炎症的组织学评估表明，到感染后第21天CVS-F3的清除与感染早期（感染后第8天）中枢神经系统中的强烈炎症反应以及快速（感染后第10天）产生高水平的病毒中和抗体（VNA）相关。这些研究证实，狂犬病VNA是清除已建立的狂犬病病毒感染的绝对必要条件。然而，为了使后者及时发生，VNA与炎症机制之间的协作是必要的。
