Department of Pathology, University of Georgia, Athens, Georgia, USA.
Adv Virus Res. 2011;79:73-89. doi: 10.1016/B978-0-12-387040-7.00005-6.
Chemokines are a family of structurally related proteins that are expressed by almost all types of nucleated cells and mediate leukocyte activation and/or chemotactic activities. The role of chemokines in rabies pathogenesis and protection has only recently been investigated. Expression of chemokines is induced by infection with laboratory-adapted, but not street, rabies viruses (RABVs), and it has been hypothesized that expression of chemokines is one of the mechanisms by which RABV is attenuated. To further define the role of chemokines in rabies pathogenesis and protection, chemokine genes such as MIP-1α, RANTES, IP-10, and macrophage-derived chemokine (MDC) have been cloned into RABV genome. It has been found that recombinant RABVs expressing RANTES or IP-10 induce high and persistent expression of these chemokines, resulting in massive infiltration of inflammatory cells into the central nervous system (CNS) and development of diseases and death in the mouse model. However, recombinant RABVs expressing MIP-1α, MDC, as well as GM-CSF further attenuate RABV by inducing a transient expression of chemokines, infiltration of inflammatory cells, enhancement of blood-brain barrier (BBB) permeability. Yet, these recombinant RABVs show increased adaptive immune responses by recruiting/activating dendritic cells, T and B cells in the periphery as well as in the CNS. Further, direct administration of these recombinant RABVs into the CNS can prevent mice from developing rabies days after infection with street RABV. All these studies together suggest that chemokines are both protective and pathogenic in RABV infections. Those with protective roles could be exploited for development of future RABV vaccines or therapeutic agents.
趋化因子是一类结构相关的蛋白家族，几乎所有有核细胞都能表达，并介导白细胞的激活和/或趋化活性。趋化因子在狂犬病发病机制和保护中的作用最近才被研究。实验室适应的但不是街头的狂犬病病毒（RABV）感染会诱导趋化因子的表达，并且有人假设趋化因子的表达是 RABV 减毒的机制之一。为了进一步确定趋化因子在狂犬病发病机制和保护中的作用，已经将趋化因子基因，如 MIP-1α、RANTES、IP-10 和巨噬细胞来源的趋化因子（MDC），克隆到 RABV 基因组中。已经发现，表达 RANTES 或 IP-10 的重组 RABV 会诱导这些趋化因子的高持续表达，导致大量炎症细胞浸润中枢神经系统（CNS），并在小鼠模型中发展为疾病和死亡。然而，表达 MIP-1α、MDC 以及 GM-CSF 的重组 RABV 通过诱导趋化因子的短暂表达、炎症细胞浸润、增强血脑屏障（BBB）通透性，进一步减毒 RABV。然而，这些重组 RABV 通过募集/激活外周和中枢神经系统中的树突状细胞、T 和 B 细胞，引起适应性免疫反应增强。此外，将这些重组 RABV 直接递送至 CNS 可以防止感染街头 RABV 后的小鼠发生狂犬病。所有这些研究都表明，趋化因子在 RABV 感染中既具有保护作用又具有致病性。那些具有保护作用的趋化因子可能被用于开发未来的 RABV 疫苗或治疗剂。
