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1、Journal of Medical Virology 35:142-149 (1991) Modulation of Coronavirus-Mediated Cell Fusion by Homeostatic Control of Cholesterol and Fatty Acid Metabolism Marguerite Cervin and Robert Anderson Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada Cellu
2、lar susceptibility to fusion mediated by mu- rine 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
3、 and fatty acid composition as did their fusion-susceptible parent subclone, and were presumably deficient in a genetically mu- table non-lipid, host cell factor (e.g., fusion pro- tein receptor). On the other hand, cellular sensi- tivity to virus fusion, which is known to be influenced by cell chol
4、esterol content Daya et al., 19881, was shown further to be modulated by homeostatic alterations in fatty acid metabolism. Cholesterol supplementation of mouse L-2 fibro- blasts or of peritoneal macrophages from MHV- susceptible mice elevated susceptibility to viral fusion. Increased fusion suscepti
5、bility occurred in cholesterol-supplemented L-2 cells in the ab- sence of any detectable alterations in host cell fatty acid composition, thus demonstrating fu- sion enhancement by cholesterol alone. L-2 cells cloned by limiting dilution in normal (not cho- lesterol-supplemented) medium were found t
6、o be heterogeneous in cholesterol content. Inter- estingly, 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:l fatty acids when compared to low choles- terol-containing subclones. High cholesterol- containing subclo
7、nes 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 observa- tions have potentially important co
8、nsequences regarding the effects of dietary cholesterol on the severity of virus infection, we examined liver titres and pathology of normal and hypercholes- terolemic mice infected with MHV. Hypercholes- terolemia had no significant effect on virus rep- lication or on liver pathology in two MHV- se
9、nsitive strains (BalbIc and AIJ) or in one MHV- 1991 WILEY-LISS, INC. resistant (SJLIJ) of mice. Lipid analyses of the livers from normal and hypercholesterolemic mice showed evidence of two homeostatic mechanisms (cholesterol esterification and alter- ation of fatty acid composition) which likely c
10、ounteracted the normally exacerbating effect of cholesterol on MHV cytopathology. INTRODUCTION Cholesterol plays an important role in determining the physical properties and functions of animal cell membranes. In addition to having a modulating effect on membrane fluidity and permeability Demel et a
11、l., 19721, there is evidence that cholesterol may interact directly with certain membrane proteins Johnson et al., 1980; Asano and Asano, 19881 and possibly regulate their functional activity McMurchie, 1988; Asano and Asano, 19881. Cholesterol is an important dietary lipid and has been shown to mod
12、ulate resistance of mice to infections by some bacteria and viruses, including Listeria mono- cytogenes Kos et al., 1979; Kos et al., 19841 and Coxsackie B virus Campbell et al., 19821 and also MHV-3 Pereira et al., 19871. MHV-3 is strongly hepa- totropic in Balb/c mice but causes only a mild liver
13、infection in A/J mice. Pereira et al. 19871, hypothe- sized that Kupffer cells (KC), the liver macrophages, are involved in resistance to MHV-3 in AIJ mice, and that such resistance may be overcome by cholesterol supplementation. This and previous studies Ruebner et al., 1958; Ruebner and Bramhall,
14、19601 on modula- tion of MHV infection by cholesterol or fats employed complex food mixtures, in which cholesterol was not the sole variable constituent. As a result it has not been possible to relate biological effects to cholesterol per se. We have shown previously Daya et al., 19881 that suppleme
15、ntation of cultured mouse L-2 fibroblasts with Accepted for publication June 19, 1991. Address reprint requests to R. Anderson, Dept. of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada. Lipid Homeostasis and Viral Fusion cholesterol results in a marked increase
16、in cellular susceptibility to fusion mediated by mouse hepatitis virus (MHV). Roos et al. 19901 have also presented evidence suggesting a role for other lipids, particularly saturatediunsaturated fatty acids, in modifying cellu- lar responsiveness to MHV-induced fusion. Since these results have potentially important consequences for the spread and severity of virus infections as a function of dietary cholesterol and other lipids, we undertook a study of cholesterol metabolism and MHV in
