Modulation of coronavirus-mediated cell fusion by homeostatic control of cholesterol and fatty acid metabolism.
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 alterations 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Cervin
M
M
Department of Microbiology and Infectious Diseases, University of Calgary, Alberta, Canada.
Anderson
R
R
D000818:Animals; D002459:Cell Fusion; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D003332:Coronaviridae / Q000254:growth & development*; D003333:Coronaviridae Infections / Q000378:metabolism / Q000382:microbiology; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000382:microbiology; D006706:Homeostasis; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008815:Mice, Inbred Strains
D002791:Cholesterol, Dietary; D005227:Fatty Acids; D002784:Cholesterol