Abstract
In 1979, Chinese scientists reported that selenium had been linked to Keshan disease, an endemic juvenile cardiomyopathy found in China. However, certain epidemiological features of the disease could not be explained solely on the basis of inadequate selenium nutrition. Fluctuations in the seasonal incidence of the disease suggested involvement of an infectious agent. Indeed, a coxsackievirus B4 isolated from a Keshan disease victim caused more heart muscle damage when inoculated into selenium-deficient mice than when given to selenium-adequate mice. Those results led us to study the relationship of nutritional status to viral virulence. Coxsackievirus B3/0 (CVB3/0), did not cause disease when inoculated into mice fed adequate levels of Se and vitamin E. However, mice fed diets deficient in either Se or vitamin E developed heart lesions when infected with CVB3/0. To determine if the change in viral phenotype was maintained, we passaged virus isolated from Se-deficient hosts, maintained, we passaged virus isolated from Se-deficient hosts, designated as CVB3/0 Se-, back into Se-adequate hosts. The CVB3/0 Se- virus caused disease in Se-adequate mice. To determine if the phenotype change was due to changes in the viral genome, we sequenced viruses isolated from Se-deficient mice and compared them with the input CVB3/0 virus. Six point mutations differed between the parent strain and the recovered CVB3/0 Se- isolates. When the experiment was repeated using vitamin E-deficient mice, the same 6 point mutations were found. This is the first report of a specific host nutritional deficiency altering viral genotype. Keshan disease may be the result of several interacting causes including a dominant nutritional deficiency (selenium), other nutritional factors (vitamin E, polyunsaturated fatty acids), and an infectious agent (virus).
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References
K. Schwarz and C. M. Foltz. Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration.J. Am. Chem. Soc. 79, 3292–3293 (1957).
Subcommittee on Selenium.Selenium in Nutrition, National Academy Press, Washington, DC (1983).
A. M. Van Rij, C. D. Thomson, J. M. McKenzie, and M. F. Robinson, Selenium deficiency in total parenteral nutrition,Am. J. Clin. Nutr. 32, 2076–2085 (1979).
Keshan Disease Research Group, Epidemiologic studies on the etiologic relationship of selenium and Keshan disease,Chin. Med. J. 92, 477–482 (1979).
G. Q. Yang, Keshan disease: an endemic selenium-related deficiency disease, inTrace Elements in Nutrition and Children, R. K. Chandra, ed., Raven, New York, pp. 273–290 (1985).
J. Bai, S. Wu, K. Ge, X. Deng and C. Su, The combined effect of selenium deficiency and viral infection on the myocardium of mice.Acta Acad. Med. Sin. 2, 29–31 (1980).
M. A. Beck, P. C. Kolbeck, Q. Shi, L. H. Rohr, V. C. Morris, and O. A. Levander. Increased virulence of a human enterovirus (coxsackievirus B3) in selenium-deficient mice.J. Infect. Dis. 170, 351–357 (1994).
M. A. Beck, P. C. Kolbeck, L. H. Rohr, Q. Shi, V. C. Morris, and O. A. Levander, Benign human enterovirus becomes virulent in selenium-deficient mice.J. Med. Virol. 43, 166–170 (1994).
N. M. Chapman, Z. Tu, S. Tracy, and C. J. Gauntt, An infectious cDNA copy of the genome of a non-cardiovirulent Coxsackievirus B3 strain-its complete sequence analysis and comparison to the genomes of cardiovirulent Coxsackieviruses,Arch. Virol. 135, 115–130 (1994).
M. A. Beck, Q. Shi, V. C. Morris, and O. A. Levander, Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates,Nature Med,1, 433–436 (1995).
M. A. Beck, P. C. Kolbeck, L. H. Rohr, Q. Shi, V. C. Morris, and O. A. Levander, Vitamin E deficiency intensifies the myocardial injury of coxsackievirus B3 infection in mice.J. Nutr. 124, 345–358 (1994).
M. A. Beck, Q. Shi, V. C. Morris, and O. A. Levander, From avirulent to virulent: vitamin E deficiency in mice drives rapid genomic evolution of a coxsackie B3 virus,FASEB J. 10, A191 (1996).
H. Dam, Interaction between vitamin E and polyunsaturated fatty acids in animals, inVitamins and Hormones, R. S. Harris and I. G. Wools, eds., Academic Press, Orlando, FL, pp. 527–540 (1962).
W. G. Hoekstra, Biochemical function of selenium and its relation to vitamin E,Fed. Proc. 34, 2083–2089 (1975).
G. Q. Yang, J. Chen, Z. Wen, K. Ge, L. Zhu, X. Chen, and X. Chen, The role of selenium in Keshan disease, inAdvances in Nutritional Research, vol. 6, H. H. Draper, ed., Plenum, New York, pp. 203–231 (1984).
G. Q. Yang, K. Ge, J. Chen, and X. Chen, Selenium-related endemic diseases and the daily selenium requirements of humans,World. Rev. Nutr. Diet. 55, 98–152 (1988).
G. F. Combs, Jr. and S. B. Combs,The Role of Selenium in Nutrition Academic Press, Orlando, FL (1986).
S. Liu and F. Wang, Study on hepatic damage induced by pathogenic factors of Keshan disease in the grains from endemic area.Chin. J. Control Endemic Dis. 5, 196–199 (1990).
S. Liu, L. Wang, Z. Zhao, and F. Wang, Alterations of histochemistry and ultrastructure in liver of rats fed with grains from a Keshan disease endemic area.J. Norman Bethune University Med. Sci. 18, 521–523 (1992).
M. D. Laryea, Y. F. Jiang, G. L. Xu, and I. Lombeck, Fatty acid composition of blood lipids in Chinese children consuming high erucic acid rapessed oil,Ann. Nutr. Metab. 36, 273–278 (1992).
M. L. Bierenbaum, Y. Chen, H. Lei, and T. Watkins, Relationship between dietary fatty acid, selenium, and degenerative cardiomyopathy,Med. Hypotheses,39, 58–62 (1992).
G. Q. He, On the etiology of Keshan disease,Chin. Med. J. 92, 416–422 (1979).
K.-Y. Ge, J. Bai, X.-J. Deng, S.-Q. Wu, S.-Q. Wang, A.-N. Xue, and C.-Q. Su, The protective effect of selenium against viral myocarditis in mice. inSelenium in Biology and Medicine, G. F. Combs, Jr. J. E. Spallholz, O. A. Levander, and J. E. Oldfield, ed., AVI New York, pp. 761–768 (1987).
G. Su, G. Gong, J. Li, C. Chen, D. Zhou, and Q. Jin, Preliminary result of viral etiological study of Keshan disease,Chin. Med. J. 59, 466–470 (1979).
Y. Li, H. Zhang, Y. Yang, H. Chen, and L. C. Archard, High prevalence of enteroviral genomic sequences in an endemic cardiomyopathy (Keshan disease) detected by nested polymerase chain reaction,Progress in Clinical Virology 1995 Joint Meeting, Prague, Czech Republic, September 10–14, p. 272 (1995).
P. D. Roath, M. A. Beck, X. Chen, A. Xue, S. Wang, and O. A. Levander, Detection of enterovirus RNA from heart tissues blocks and blood obtained from a Keshan disease endemic area of China using reverse transcriptase-polymerase chain reaction (RT-PCR),FASEB J. 10, A3213 (1996).
K. Y. Ge, A. Xue, J. Bai, and S. Wang, Keshan disease-an endemic cardiomyopathy in China,Virchows Arch. (Pathol. Anat.) 401, 1–15 (1983).
G. S. Li, F. Wang, D. Kang, and C. Li, Keshan disease: an endemic cardiomyopathy in China,Hum. Pathol. 16, 602–609 (1985).
F. Y. Yang, Z. H. Lin, S. G. Li, B. Q. Guo, and Y. S. Yin, Keshan disease—an endemic mitochondrial cardiomyopathy in China,J. Trace Element Electrolytes Health Dis. 2, 157–163 (1988).
F.-Y. Yang, Z-H. Lin, J.-R. Xing, S.-G. Li, J. Yang, S. San, and L.-Y. Wu, Se deficiency is a necessary but not sufficient factor required for the pathogenesis of Keshan disease,J. Clin. Biochem. Nutr. 16, 101–110 (1994).
K. Schwarz, Vitamin E, trace elements and sulfhydryl groups in respiratory decline (an approach to the mode of action of tocopherol and related compounds),Vitam. Horm. 20, 463–484 (1962).
O. A. Levander, V. C. Morris, and D. J. Higgs, Selenium as a catalyst for the reduction of cytochrome c by glutathione,Biochemistry 12, 4591–4595 (1973).
D. Kang, G. Li, F. Wang, and G. Yang, Pancreatic lesions of Keshan disease and its significances,Chin. Med. J. 100, 671–676 (1987).
G. F. Combs, Jr., C. H. Liu, Z. H. Lu, and Q. Su, Uncomplicated selenium deficiency produced in chicks fed a corn-soy-based diet,J. Nutr. 114, 964 (1984).
M. Solimena and P. DeCamilli, Coxsackieviruses and diabetes,Nature Med. 1 25–26 (1995).
R. M. Gomez, X. Cui, C. G. Castagnino, and M. I. Berria, Differential behavour in pancreas and heart of two coxsackievirus B3 variants,Intervirology 36, 153–160 (1993).
T. Taksdal, T. Poppe, T. Sivertsen, and H. W. Ferguson, Low levels of vitamin E in plasma from Atlantic salmonSalmo salar with acute infectious pancreatic necrosis (IPN),Dis. Aquatic Organisms 22, 33–37 (1995).
N. S. Scrimshaw, C. E. Taylor, and J. E. Gordon,Interactions of Nutrition and Infection, World Health Organization, Geneva (1968).
J. F. Woodruff and E. D. Kilbourne, The influence of quantitated post-weaning under-nutrition on coxsackievirus B3 infection of adult mice. I. Viral persistence and increased severity of lesions,J. Infect. Dis. 121, 137–163 (1970).
J. F. Woodruff, The influence of quantitated post-weaning undernutrition on coxsackievirus B3 of adult mice. II. Alteration of host defense mechanisms,J. Infect. Dis. 121, 164–181 (1970).
D. L. Snyder, ed.,Dietary Restriction and Aging, Alan R. Liss, New York (1988).
Anonymous, Energy intake restriction and oxidant defense,Nutr. Rev. 49, 278–280 (1991).
H. H. Draper and A. S. Csallany, Action ofN′ N′-diphenyl-p-phenylenediamine in tocopherol deficiency diseases,Proc. Soc. Exp. Biol. Med. 99, 739–742 (1958).
Y. Hiraoka, C. Kishimoto, K. Masahiko, H. Ochiai, and S. Sasayama, Effects of polyethylene glycol conjugated superoxide dismutase on coxsackievirus B3 myocarditis in mice,Cardiovas. Res. 26, 956–961 (1992).
Y. Chen, J. T. Saari, and Y. J. Kang, Weak antioxidant defenses make the heart a target for damage in copper-deficient rats,Free Radical Biol. Med. 17, 529–536 (1994).
K. Schwarz, Development and status of experimental work on Factor 3-selenium,Fed. Proc. 20, 666–673 (1961).
K. Schwarz, Selenium and Kwashiorkor,Lancet 1335–1336 (1965).
A. S. Majaj and L. L. Hopkins, Jr., Selenium Kwashiorkor,Lancet 592–593 (1966).
L. L. Hopkins, Jr. and A. S. Majaj, Selenium in human nutrition, inSelenium in Biomedicine, O. H. Muth, J. E. Oldfield, and P. H. Weswig, eds., AVI, Westport, CT, pp. 203–214 (1967).
R. F. Burk, Jr., W. N. Pearson, R. P. Wood, and F. Viteri, Blood-selenium levels and in vitro red blood cell uptake of75Se in Kwashiorkor,Am. J. Clin. Nutr. 20, 723–733 (1967).
M. H. N. Golden and D. Ramdath, Free radicals in the pathogenesis of Kwashiorkor, inProceedings of the XIII International Congress of Nutrition, T. G. Taylor and N. K. Jenkins, eds., John Libbey, London, pp. 597–598 (1985).
M. H. N. Golden and D. Ramdath, Free radicals in the pathogenesis of Kwashiorkor,Proc. Nutr. Soc. 46, 53–68 (1987).
A. A. Sive, H. De, V. Heese, W. S. Dempster, E. Subotsky, H. Malan, and R. Sacks, Protein energy malnutrition: selenium, glutathione peroxidase and glutathione in children with acute kwashiorkor and during refeeding, inTrace Elements in Man and Animals 7, B. Momcilovic, ed., IMI, Zagreb, pp. 19–15, 19–16 (1991).
H. M. Ahmed, I. Lombec, A. O. El-Karib, E. O. El-Amin, H. Menzel, D. Frosch, M. Leichsenring, and H. J. Bremer, Selenium status in Sudanese children with protein-calorie malnutrition,J. Trace Elem. Electrolytes Health Dis. 3, 171–174 (1989).
R. Albrecht and M. A. Pelissier, About the oxidative stress status in children with Kwashiorkor,Food Chem. Toxic. 33, 1081–1083 (1995).
N.-G. Ilback, J. Fohlman, and G. Friman, Protective effect of selenium on the development of coxsackie virus B3-induced inflammatory lesions in the murine myocardium,J. Trace Element Expl. Med. 2, 257–266 (1989).
National Research Council, Committee on Medical and Biologic Effects of Environmental Pollutants,Selenium, National Academy Press, Washington, DC (1976).
N.-O. Ilback, J. Fohlman, and G. Friman, Selenium (Se) supplementation decreases myocardial injury and increases survival in coxsackie B3 (CB3) virus infected mice,J. Invest. Med. 43, 269A (1995).
J. Parizek, J. Kalouskova, J. Benes, and L. Pavlik, Interactions of selenium-mercury and selenium-selenium compounds, inMicronutrient Interactions: Vitamins, Minerals and Hazardous Elements, O. A. Levander and L. Chen, eds., The New York Academy of Sciences, New York, pp. 347–360 (1980).
P. D. Whanger, J. W. Ridlington, and C. L. Holcomb, Interactions of zinc and selenium on the binding of cadmium to rat tissue proteins, inMicronutrient Interactions: Vitamins, Mineral and Hazardous Elements, O. A. Levander and L. Cheng, eds., The New York Academy of Sciences, New York, pp. 333–346 (1980).
N.-G. Ilback, U. Lindh, L. Wessleo, J. Fohlman, and G. Friman, Heart trace elements are changed after viral infection (coxsackie B3) in methyl mercury exposed mice,J. Invest. Med. 43, 269A (1995).
N.-G. Ilback, J. Fohlman, G. Friman, and A. W. Glynn, Altered distribution of109cadmium in mice during viral infection,Toxicology 71, 193–202 (1992).
J. Parizek, I. Ostadalova, J. Kalouskova, A. Babicky, and J. Benes, The detoxifying effects of selenium interrelations between compounds of selenium and certain metals, inNewer Trace Elements in Nutrition, W. Mertz and W. E. Cornatzer, eds., Marcel Dekker, New York, pp. 85–122 (1971).
R. M. Loria, S. Kibrick, and G. E. Madge, Infection of hypercholesterolemic mice with coxsackievirus B,J. Infect. Dis. 133, 655–662 (1976).
N.-G. Ilback, A. Mohammed, J. Fohlman, and G. Friman, Cardiovascular lipid accumulation with coxsackie B virus infection in mice,Am. J. Pathol. 136, 159–167 (1990).
J. Holland, Replication error, quasispecies populations, and extreme evolution rates of RNA viruses, inEmerging Viruses, S. S. Morse, ed., Oxford University Press, New York, pp. 203–218 (1993).
E. D. Kilbourne, Afterword: a personal summary presented as a guide for discussion, inEmerging Viruses, S. S. Morse, ed., Oxford University Press, New York, pp. 290–294 (1993).
P. Adler, Preventing polio: don’t tamper with success,Washington Post April 2 (1996).
S. L. Katz, A vaccine riskier than the disease,The Washington Post April 26 (1996).
D. Drollete, Australia fends off critic of plan to eradicate rabbits,Science 272, 191–192 (1996).
J. Kaiser, Australia postpones rabbit virus release,Science 272, 341 (1996).
N. D. Costa, H. G. Masters, P. Steele, B. J. Hilbert, J. F. Hudman, and J. R. Bolton, The selenium status of horses in Western Australia, inTrace Element Metabolism in Man and Animals, J. McC. Howell, J. M. Gawthorne, and C. L. White, eds., Australian Academy of Science, Canberra, pp. 44–46 (1981).
K. O. Godwin, The role and the metabolism of selenium in the animal, inTrace Elements in Soil-Plant-Animal Systems, D. J. D. Nicholas and A. R. Egan, eds., Academic, New York, pp. 259–270 (1975).
S. F. Arnold, D. M. Klotz, B. M. Collins, P. M. Vonier, L. J. Guillette, Jr., and J. A. McLachlan, Synergistic activation of estrogen receptor with combinations of environmental chemicals,Science 272, 1489–1492 (1996).
C. Suplee, “Environmental estrogens” may pose greater risk, study shows,Washington Post June 7 (1996).
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Levander, O.A., Beck, M.A. Interacting nutritional and infectious etiologies of Keshan disease. Biol Trace Elem Res 56, 5–21 (1997). https://doi.org/10.1007/BF02778980
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DOI: https://doi.org/10.1007/BF02778980