Askovic S, Favara C, McAtee F J, Portis J L
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA.
J Virol. 2001 Mar;75(6):2665-74. doi: 10.1128/JVI.75.6.2665-2674.2001.
The chimeric murine oncornavirus FrCas(E) causes a rapidly progressive paralytic disease associated with spongiform neurodegeneration throughout the neuroaxis. Neurovirulence is determined by the sequence of the viral envelope gene and by the capacity of the virus to infect microglia. The neurocytopathic effect of this virus appears to be indirect, since the cells which degenerate are not infected. In the present study we have examined the possible role of inflammatory responses in this disease and have used as a control the virus F43. F43 is an highly neuroinvasive but avirulent virus which differs from FrCas(E) only in 3' pol and env sequences. Like FrCas(E), F43 infects large numbers of microglial cells, but it does not induce spongiform neurodegeneration. RNAase protection assays were used to detect differential expression of genes encoding a variety of cytokines, chemokines, and inflammatory cell-specific markers. Tumor necrosis factor alpha (TNF-alpha) and TNF-beta mRNAs were upregulated in advanced stages of disease but not early, even in regions with prominent spongiosis. Surprisingly there was no evidence for upregulation of the cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-6 or of the microglial marker F4/80 at any stage of this disease. In contrast, increased levels of the beta-chemokines MIP-1 alpha and -beta were seen early in the disease and were concentrated in regions of the brain rich in spongiosis, and the magnitude of responses was similar to that observed in the brains of mice injected with the glutamatergic neurotoxin ibotenic acid. MIP-1alpha and MIP-1beta mRNAs were also upregulated in F43-inoculated mice, but the responses were three- to fivefold lower and occurred later in the course of infection than was observed in FrCas(E)-inoculated mice. These results suggest that the robust increase in expression of MIP-1 alpha and MIP-1 beta in the brain represents a correlate of neurovirulence in this disease, whereas the TNF responses are likely secondary events.
嵌合鼠致癌RNA病毒FrCas(E)可引发一种快速进展的麻痹性疾病，该疾病与整个神经轴的海绵状神经变性有关。神经毒性由病毒包膜基因的序列以及病毒感染小胶质细胞的能力决定。这种病毒的神经细胞病变效应似乎是间接的，因为退化的细胞并未被感染。在本研究中，我们研究了炎症反应在该疾病中可能发挥的作用，并使用病毒F43作为对照。F43是一种高度神经侵袭性但无毒的病毒，它与FrCas(E)的区别仅在于3'端的pol和env序列。与FrCas(E)一样，F43可感染大量小胶质细胞，但不会诱导海绵状神经变性。核糖核酸酶保护分析用于检测编码多种细胞因子、趋化因子和炎症细胞特异性标志物的基因的差异表达。肿瘤坏死因子α（TNF-α）和TNF-β的信使核糖核酸（mRNA）在疾病晚期上调，但早期没有，即使在海绵样变明显的区域也是如此。令人惊讶的是，在该疾病的任何阶段，均未发现细胞因子白细胞介素-1α（IL-1α）、IL-1β和IL-6或小胶质细胞标志物F4/80上调的证据。相反，β趋化因子MIP-1α和-β在疾病早期水平升高，并集中在富含海绵样变的脑区，其反应程度与注射谷氨酸能神经毒素鹅膏蕈氨酸的小鼠脑中观察到的相似。在接种F43的小鼠中，MIP-1α和MIP-1β的mRNA也上调，但与接种FrCas(E)的小鼠相比，反应低三到五倍，且在感染过程中出现得更晚。这些结果表明，脑中MIP-1α和MIP-1β表达的强烈增加代表了该疾病中神经毒性的一个相关因素，而TNF反应可能是继发事件。
