Abstract
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 i n 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 i n 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:l 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 AIJ) or in one MHV‐resistant (SJLIJ) 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.
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References
- Allison AC (1974): On the role of mononuclear phagocytes in immunity against viruses. Progress in Medical Virology 18: 15. [PubMed] [Google Scholar]
- Arnheiter H, Baechi T, Haller O (1982): Adult mouse hepatocytes in primary monolayer culture express genetic resistance to mouse hepatitis virus type 3. Journal of Immunology 129: 1275–1281. [PubMed] [Google Scholar]
- Asano K, Asano A (1988): Binding of cholesterol and inhibitory peptide derivatives with the fusogenic hydrophobic sequence of F‐glycoprotein of HVJ (Sendai virus): Possible implication in the fusion reaction. Biochemistry 27: 1321–1329. [DOI] [PubMed] [Google Scholar]
- Campbell AE, Loria RM, Madge GE, Kaplan AM (1982): Dietary hepatic cholesterol elevation: Effects on coxsackie B infection and inflammation. Infection and Immunity 37: 307–317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daya M, Cervin M, Anderson R (1988): Cholesterol enhances mouse hepatitis virus‐mediated cell fusion. Virology 163: 276–283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daya M, Wong F, Cervin M, Evans G, Vennema H, Spaan W, Anderson R (1989): Mutation of host cell determinants which discriminate between lytic and persistent mouse hepatitis virus infection results in a fusion‐resistant phenotype. Journal of General Virology 70: 3335–3346. [DOI] [PubMed] [Google Scholar]
- Demel RA, Geurts van Kessel WSM, van Deenen LLM (1972): The properties of polyunsaturated lecithins in monolayers and liposomes and the interaction of those lecithins with cholesterol. Biochimica et Biophysica Acta 266: 26–40. [DOI] [PubMed] [Google Scholar]
- Fillios LC, Andrus SB, Mann GV, Stare FJ (1956): Experimental production of gross atherosclerosis in the rat. Journal of Experimental Medicine 104: 539–554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frank JS, Fogelman AM (1989): Ultrastructure of the intima in WHHL and cholesterol‐fed rabbit aortas prepared by ultra‐rapid freezing and freeze‐etching. Journal of Lipid Research 30: 967–973. [PubMed] [Google Scholar]
- Garg L, Sabine JR (1988): Homoeostatic control of membrane cholesterol and fatty acid metabolism in the rat liver. Biochemical Journal 251: 11–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnson MK, Geoffroy C, Alouf JE (1980): Binding of cholesterol by sulfhydryl‐activated cytolysins. Infection and Immunity 27: 97–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kos WL, Loria RM, Snodgrass MJ, Cohen D, Thorpe TG, Kaplan AM (1979): Inhibition of host resistance by nutritional hypercholesteremia. Infection and Immunity 26: 658–667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kos WL, Kos KA, Kaplan AM (1984): Impaired function of immune reactivity to Listeria monocytogenes in diet‐fed mice. Infection and Immunity 43: 1094–1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loria RM, Kibrick S, Madge GE (1976): Infection of hypercholesterolemic mice with coxsackie B. Journal of Infectious Diseases 133: 655–662. [DOI] [PubMed] [Google Scholar]
- Manaker RA, Piczak CV, Miller AA, Stanton MF (1961): A hepatitis virus complicating studies with mouse leukemia. Journal of the National Cancer Institute 27: 29–44. [PubMed] [Google Scholar]
- McMurchie EJ (1988): Dietary lipids and the regulation of membrane fluidity and function In: “Physiological Regulation of Membrane Fluidity,” Chapter 7 New York: Alan R. Liss, pp 189–237. [Google Scholar]
- Mims CA (1964): Aspects of the pathogenesis of virus diseases. Bacteriological Reviews 28: 30–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mizzen L, Cheley S, Rao M, Wolf R, Anderson R (1983): Fusion resistance and decreased infectability as major host cell determinants of corona virus persistence. Virology 128: 407–417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pereira CA, Steffan AM, Koehren F, Douglas CR, Kirn A (1987): Increased susceptibility of mice to MHV‐3 infection induced by hypercholesterolemic diet: Impairment of kupffer cell function. Immunobiology 174: 253–265. [DOI] [PubMed] [Google Scholar]
- Roos DS, Duchale CS, Stephensen CB, Holmes KV, Choppin PW (1990): Control of virus‐induced cell fusion by host cell lipid composition. Virology 175: 345–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rothfels KH, Axelrad AA, Siminovitch L, McCulloch EA, Parker RC (1959): The origin of altered cell lines from mouse, monkey and man as indicated by chromosome and transplantation studies. Canadian Cancer Conference 3: 189–214. [Google Scholar]
- Ruebner BH, Bramhall JL, Berry GR (1958): Experimental virus hepatitis in choline‐deficient mice with fatty livers. Archives of Pathology and Laboratory Medicine 66: 165. [PubMed] [Google Scholar]
- Ruebner BH, Bramhall JL (1960): The effect of changes in dietary protein on experimental viral hepatitis in mice. Gastroenterology 39: 335. [PubMed] [Google Scholar]
- Sabesin SM, Koft RS (1974): Pathogenesis of experimental viral hepatitis. New England Journal of Medicine 290: 944–950. [DOI] [PubMed] [Google Scholar]
- Smith MS, Click RE, Plagemann RGW (1984): Control of mouse hepatitis virus replication in macrophages by a recessive gene on chromosome 7. Journal of Immunology 133: 428–432. [PubMed] [Google Scholar]
- Virelizier JL, Allison AC (1976): Correlation of persistent mouse hepatitis (MHV‐3) infection with its effects on mouse macrophage cultures. Archives of Virology 50: 279–285. [DOI] [PMC free article] [PubMed] [Google Scholar]