Hickey Michelle J, Held Katherine S, Baum Elizabeth, Gao Ji-Liang, Murphy Philip M, Lane Thomas E
Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, California 92697-3900, USA.
Viral Immunol. 2007 Dec;20(4):599-608. doi: 10.1089/vim.2007.0056.
The role of CC chemokine receptor 1 (CCR1) in host defense and disease development was determined in a model of viral-induced neurologic disease. Intracerebral (IC) infection of mice with mouse hepatitis virus (MHV) results in an acute encephalitis followed by a chronic demyelinating disease similar in pathology to the disease multiple sclerosis (MS). No increase in mortality was observed during the acute phase of disease following MHV infection of mice lacking CCR1 (CCR1-/-) as compared to wild-type (CCR1+/+) mice. However, by 21 d post-infection, 74% of CCR1-/- mice had succumbed to death compared to only 32% mortality of CCR1+/+ mice, indicating that chemokine signaling through CCR1 significantly (p <or= 0.04) enhanced survival following IC infection with MHV. Increased mortality in CCR1-/- mice was not associated with increased viral recovery from the CNS, although CCR1 deficiency correlated with reduced T-cell accumulation within the CNS during acute, but not chronic, disease. Despite the reduction in T-cell trafficking into the CNS of CCR1-/- mice during acute disease, components of host defense remained unaltered; T-cell effector functions including cytolytic activity and proliferation and the expression of IFN-gamma within the CNS were not significantly different between CCR1+/+ and CCR1-/- infected mice. In addition, macrophage infiltration into the CNS was unaffected in MHV-infected CCR1-/- mice when compared to CCR1+/+ mice. Furthermore, assessment of neuropathology revealed no difference in the severity of demyelination between CCR1-deficient and wild-type mice. Together, these findings reveal that T-cell and macrophage trafficking are not dependent on CCR1 and highlight an important role for CCR1 signaling in promoting survival during chronic MHV infection.
在一种病毒诱导的神经疾病模型中，确定了CC趋化因子受体1（CCR1）在宿主防御和疾病发展中的作用。用小鼠肝炎病毒（MHV）对小鼠进行脑内（IC）感染会导致急性脑炎，随后引发一种慢性脱髓鞘疾病，其病理与多发性硬化症（MS）相似。与野生型（CCR1+/+）小鼠相比，缺乏CCR1的小鼠（CCR1-/-）在感染MHV后的疾病急性期未观察到死亡率增加。然而，感染后21天时，74%的CCR1-/-小鼠死亡，而CCR1+/+小鼠的死亡率仅为32%，这表明通过CCR1的趋化因子信号显著（p≤0.04）提高了脑内感染MHV后的生存率。CCR1-/-小鼠死亡率的增加与从CNS中病毒回收的增加无关，尽管CCR1缺陷与急性（而非慢性）疾病期间CNS内T细胞积累的减少相关。尽管在急性疾病期间CCR1-/-小鼠进入CNS的T细胞运输减少，但宿主防御的组成部分未发生改变；CCR1+/+和CCR1-/-感染小鼠之间，包括细胞溶解活性和增殖在内的T细胞效应功能以及CNS内IFN-γ的表达没有显著差异。此外，与CCR1+/+小鼠相比，MHV感染的CCR1-/-小鼠中巨噬细胞向CNS的浸润未受影响。此外，神经病理学评估显示CCR1缺陷小鼠和野生型小鼠之间脱髓鞘严重程度没有差异。总之，这些发现表明T细胞和巨噬细胞运输不依赖于CCR1，并突出了CCR1信号在慢性MHV感染期间促进生存中的重要作用。
