MODULATION OF CORONAVIRUS-MEDIATED CELL-FUSION BY HOMEOSTATIC CONTROL OF CHOLESTEROL AND FATTY-ACID METABOLISM
MODULATION OF CORONAVIRUS-MEDIATED CELL-FUSION BY HOMEOSTATIC CONTROL OF CHOLESTEROL AND FATTY-ACID METABOLISM
复制标题
DOI：
10.1002/jmv.1890350213
复制
发表时间：
1991-10-01
影响因子：
12.7
通讯作者：
ANDERSON, R
中科院分区：
文献类型：
--
作者：
CERVIN, M;ANDERSON, R
利用小鼠L-2成纤维细胞的亚克隆和选定的突变体，将细胞对鼠冠状病毒（小鼠肝炎病毒，MHV株A59）介导的融合的易感性分为脂质依赖性和脂质非依赖性机制。 融合抗性L-2细胞突变体具有与它们的融合易感亲本亚克隆相似的胆固醇和脂肪酸组成，并且推测缺乏遗传可变的非脂质宿主细胞因子（例如，融合蛋白受体）。 另一方面，已知细胞对病毒融合的敏感性受细胞胆固醇含量的影响[Daya等人，1988]进一步显示通过脂肪酸代谢中的稳态改变来调节。 小鼠L-2成纤维细胞或MHV易感小鼠的腹腔巨噬细胞的胆固醇补充增加了对病毒融合的易感性。 增加的融合易感性发生在胆固醇补充的L-2细胞中的宿主细胞脂肪酸组成的任何可检测的变化的情况下，从而证明单独胆固醇的融合增强。 L-2细胞克隆有限稀释在正常（不补充胆固醇）培养基中被发现是异质性的胆固醇含量。 有趣的是，与低胆固醇亚克隆相比，高胆固醇亚克隆具有增加的C-18：0、C-18：2、C-20：4和C-22：6的水平，以及显著降低的C-18：1脂肪酸的水平。 高胆固醇含量的亚克隆没有表现出增强的病毒融合的易感性，这表明脂肪酸代谢的稳态改变补偿了胆固醇水平的增加，并抵消了胆固醇单独的正常融合增强作用。 由于这些观察结果对饮食胆固醇对病毒感染严重程度的影响具有潜在的重要影响，我们检查了感染MHV的正常和高胆固醇血症小鼠的肝脏滴度和病理学。 高胆固醇血症对两种MHV敏感株（Balb/c和A/J）或一种MHV耐药小鼠（SJL/J）的病毒复制或肝脏病理学无显著影响。 正常和高胆固醇血症小鼠肝脏的脂质分析显示了两种稳态机制（胆固醇酯化和脂肪酸组成改变）的证据，这可能会抵消胆固醇对MHV细胞病理学的正常加重作用。
Cellular susceptibility to fusion mediated by murine coronavirus (mouse hepatitis virus, MHV strain A59) was separated into lipid-dependent and lipid-independent mechanisms with the use of subclones and selected mutants of mouse L-2 fibroblasts. Fusion-resistant L-2 cell mutants had similar cholesterol and fatty acid composition as did their fusion-susceptible parent subclone, and were presumably deficient in a genetically mutable non-lipid, host cell factor (e.g., fusion protein receptor). On the other hand, cellular sensitivity to virus fusion, which is known to be influenced by cell cholesterol content [Daya et al., 1988], was shown further to be modulated by homeostatic alterations in fatty acid metabolism. Cholesterol supplementation of mouse L-2 fibroblasts or of peritoneal macrophages from MHV-susceptible mice elevated susceptibility to viral fusion. Increased fusion susceptibility occurred in cholesterol-supplemented L-2 cells in the absence of any detectable alternations in host cell fatty acid composition, thus demonstrating fusion enhancement by cholesterol alone. L-2 cells cloned by limiting dilution in normal (not cholesterol-supplemented) medium were found to be heterogeneous in cholesterol content. Interestingly, high cholesterol-containing subclones had increased levels of C-18:0, C-18:2, C-20:4, and C-22:6 and markedly reduced levels of C-18:1 fatty acids when compared to low cholesterol-containing subclones. High cholesterol-containing subclones did not show enhanced susceptibility to viral fusion, suggesting that homeostatic alteration of fatty acid metabolism compensated for the increased cholesterol levels and countered the normally fusion-enhancing effect of cholesterol alone. Since these observations have potentially important consequences regarding the effects of dietary cholesterol on the severity of virus infection, we examined liver titres and pathology of normal and hypercholesterolemic mice infected with MHV. Hypercholesterolemia had no significant effect on virus replication or on liver pathology in two MHV-sensitive strains (Balb/c and A/J) or in one MHV-resistant (SJL/J) of mice. Lipid analyses of the livers from normal and hypercholesterolemic mice showed evidence of two homeostatic mechanisms (cholesterol esterification and alteration of fatty acid composition) which likely counteracted the normally exacerbating effect of cholesterol on MHV cytopathology.