Antiviral and Immunomodulatory Activities of Ascorbic Acid

  • Raxit J. Jariwalla
  • Steve Harakeh
Part of the Subcellular Biochemistry book series (SCBI, volume 25)

Abstract

It has been known since the early days of ascorbic acid research that the appearance of scurvy, which is caused by deficiency of this vitamin, is associated with decreased resistance to infection (Reid and Briggs, 1953). Over the years, it has become well recognized that ascorbate can bolster the natural defense mechanisms of the host and provide protection not only against infectious disease, but also against cancer and other chronic degenerative diseases. The functions involved in ascorbate’s enhancement of host resistance to disease include its biosynthetic (hy-droxylating), antioxidant, and immunostimulatory activities. In addition, ascorbate exerts a direct antiviral action that may confer specific protection against viral disease. The vitamin has been found to inactivate a wide spectrum of viruses as well as suppress viral replication abd expression in infected cell. In this article we review the antiviral and immunotimulatory effects of ascorbate and their relevance to control of acute and chronic viral infections. Detailed discussion of thr biosynthetic activities of ascorbate has been presented in a review by England and Seifter (1986). The antinoxidant function of ascorbate has been reviewed recently by Bendich (1988)

Keywords

Hepatitis Leukemia Glutathione Pneumonia Superoxide 

Abbreviations

AZT

3′-azidothymidine

CD

cluster of differentiation

CHS

Chediak-Higashi syndrome

Con A

concanavalin-A

EAE

experimental allergic encephalomyelitis

HIV

human immunodeficiency virus

HTLV-1

human T-cell leukemia virus-1

HTLV-1

human T-cell leukemia virus-1

IL

interleukin

INF

interferon

NAC

N-acetyl cysteine

NF-kB

neurotrophic factor-k beta

PBMC

peripheral blood mononuclear cells

PMA

phorbol 12-myristate 13-acetate

PMN

polymorphonuclear neutrophil

RT

reverse transcriptase

TNF-2

tumor necrosis factor alpha

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson, R., 1981a, Ascorbic acid and immune functions: Mechanism of immunostimulation, in Vitamin C (Ascorbic Acid) (J. N. Counsell and D. H. Hornig, eds.), pp. 249–272, Applied Science, London.Google Scholar
  2. Anderson, R., 1981b, Assessment of oral ascorbate in three children with chronic granulomatous disease and defective neutrophil motility over a 2-year period, Clin. Exp. Immunol. 43:180.PubMedGoogle Scholar
  3. Anderson, R., Oosthuizen, R., Maritz, R., Theron, A., and Van Rensburg, A. J., 1980, The effects of increasing weekly doses of ascorbic acid on certain cellular and humoral immune functions in normal volunteers, Am. J. Clin. Nutr. 33:71.PubMedGoogle Scholar
  4. Anderson, R., and Theron, A., 1979, Effects of ascorbate on leukocytes. I. Effects of ascorbate on neutrophil motility and intracellular cyclic nucleotide levels in vitro, S. Afr. Med. J. 56:394.PubMedGoogle Scholar
  5. Anderson, R., and Lukey, P. T., 1987, A biological role for ascorbate in the selective neutralization of extracellular phagocyte-derived oxidants, Ann. N.Y. Acad. Sci. 498:229–247.PubMedCrossRefGoogle Scholar
  6. Anderson, R., Hay, I., Van Wyk, H. A., and Theron, A., 1983, Ascorbic acid in bronchial asthma, S. Afr. Med. J. 63:649.PubMedGoogle Scholar
  7. Anderson, R., Lukey, P. T., Theron, A. J., and Dippenaar, U., 1987, Ascorbate and cysteine-mediated selective neutralization of extracellular oxidants during N-formyl peptide activation of human phagocytes, Agents Actions 10:77–86.CrossRefGoogle Scholar
  8. Anthony, L. E., Kurahara, C. C, and Taylor, K. B., 1979, Cell mediated cytotoxicity and humoral immune response in ascorbic acid deficient guinea pigs. Am. J. Clin. Nutr. 32:1691.PubMedGoogle Scholar
  9. Baehner, R. L., 1980, Neutrophil dysfunction associated with states of chronic and recurrent infections, Pediatr. Clin. North Am. 27:377.PubMedGoogle Scholar
  10. Bendich, A., 1988, Antioxidants, vitamins and immunity, in Nutrition and Immunology (R. Chandra, ed.), p. 125, Liss, New York.Google Scholar
  11. Bendich, A., D’Apolito, P., Gabriel, E., and Machlin, C. J., 1984, Interaction of dietary vitamin C and vitamin E on guinea pig immune responses to mitogen, J. Nutr. 114:1588.Google Scholar
  12. Bissell, M. J., Hatie, C, Farson, D. A., Schwarz, R. I., and Soo, W., 1980, Ascorbic acid inhibits replication and infectivity of avian RNA tumor virus, Proc. Natl. Acad. Sci. USA 77:2711.PubMedCrossRefGoogle Scholar
  13. Blakeslee, J. R., Yamamoto, N., and Hinuma, Y., 1985, Human T-cell leukemia virus 1 induction by 5-iodo-2′-deoxyuridine and N-methyl-N’-nitro-N-nitrosoguanidine: Inhibition by retinoids, 1-ascorbic acid and dl-alpha tocopherol, Cancer Res. 45:3471.PubMedGoogle Scholar
  14. Boxer, L. A., Vanderbilt, B., Bonsib, S., Jersild, R., Yang, H. H., and Baehner, R. L., 1979, Enhancement of chemotactic response and microtibule assembly in human leukocytes by ascorbic acid, J. Cell. Physiol. 100:119–126.PubMedCrossRefGoogle Scholar
  15. Boxer, L. A., Watanabe, A. M., Rister, M., Besch Jr., H. R., Allen, J., and Baehner, R. L., 1976. Correction of leukocyte function in Chediak-Higashi Syndrome by ascorbate, N. Engl. J. Med. 295:1041.PubMedCrossRefGoogle Scholar
  16. Cameron, E., Pauling, L., and Leibovitz, B., 1979, Ascorbic acid and cancer: A review, Cancer Res. 39:663.PubMedGoogle Scholar
  17. Cathcart, R. F., 1981, Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy, Med. Hypoth. 7:1359–1376.CrossRefGoogle Scholar
  18. Cathcart, R. F., 1984, Vitamin C in the treatment of acquired immune deficiency syndrome (AIDS), Med. Hypoth. 14:423.CrossRefGoogle Scholar
  19. Cathcart, R. F., 1990, Glutathione and HIV infection, Lancet 335:235.Google Scholar
  20. Chandra, R. K., 1992, Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects, Lancet 340:1124.PubMedCrossRefGoogle Scholar
  21. Cunningham-Rundles, W. F., Berner, Y., and Cunningham-Rundles, S., 1993, Interaction of vitamin C in lymphocyte activation, in Nutrient Modulation of the Immune Response (S. Cunningham-Rundles, ed.), pp. 91–104, Marcel Dekker, Inc., New York.Google Scholar
  22. Dahl, H., and Degre, M., 1976, The effect of ascorbic acid on production of human interferon and the antiviral activity in vitro, Acta Pathol. Microbiol. Immunol. Scand. 84:280.Google Scholar
  23. Dallegri, F., Lanzi, G., and Patarone, F., 1980, Effects of ascorbic acid on neutrophil locomotion, Arch. Allergy Appl. Immunol. 61:40–45.CrossRefGoogle Scholar
  24. DeChatelet, L. R., Cooper, R. M., and McCall, C. E., 1972, Stimulation of the hexose monophosphate shunt in human neutrophils by ascorbic acid: Mechanism of action, Antimicrob. Agents Chemother., 1:12.PubMedGoogle Scholar
  25. Delafuente, J. C, and Panush, R. S., 1979, Modulation of certain immunologic responses by vitamin C. II. Enhancement of concanavalin A-stimulated lymphocyte responses, Int. J. Vitam. Nutr. Res., 50:44.Google Scholar
  26. Dieter, M. P., 1971, Further studies on the relationship between vitamin C and thymic humoral factor, Proc. Soc. Exp. Biol. Med. 136:316.PubMedGoogle Scholar
  27. Dieter, M. P., and Breitenbach, R. P., 1971, Vitamin C in lymphoid organs of rats and cockerels treated with corticosterone or testosterone, Proc. Soc. Exp. Biol. Med. 137:341.PubMedGoogle Scholar
  28. Englard, S., and Seifter, S., 1986, The biochemical functions of ascorbic acid, Annu. Rev. Nutr. 6:365.PubMedCrossRefGoogle Scholar
  29. Feigen, G. A., Smith, B. H., Dix, C. E., Flynn, C. J., Peterson, N. S., Rosenberg, L. T., Pavlovic, S., and Leibovitz, B., 1982, Enhancement of antibody production and protection against systemic anaphylaxis by large doses of vitamin C, Res. Commun. Chem. Pathol. Pharmacol. 38:313.PubMedGoogle Scholar
  30. Fraser, R. C, Parlovic, S., Kurahara, CG., Murata, A., Peterson, N. S., Taylor, K. B., and Feigen, C. A., 1978, The effect of variations in vitamin C intake on the cellular immune response of guinea pigs, Am. J. Clin. Nutr. 33:839.Google Scholar
  31. Gatner, E. M. S., and Anderson, R., 1980, An in vitro assessment of cellular and humoral immune function in pulmonary tuberculosis: Correction of defective neutrophil motility by ascorbate, levamisole, metoprolol and propranolol, Clin. Exp. Immunol. 40:372.Google Scholar
  32. Goetzl, E. J., 1976, Defective responsiveness to ascorbic acid of neutrophil random and chemotactic migration in Felty’s syndrome and systemic lupus erythematosus, Ann. Rheum. Dis. 35:510.PubMedCrossRefGoogle Scholar
  33. Goetzl, E. J., Wasserman, S. I., Gigli, I., and Austen, K. F., 1974, Enhancement of random migration and chemotactic response of human leukocytes by ascorbic acid, J. Clin. Invest. 53:813–818.PubMedCrossRefGoogle Scholar
  34. Goodwin, J. S., and Garry, P. J., 1983, Relationship between megadose vitamin supplementation and immunological function in a healthy elderly population, Clin. Exp. Immunol. 51:647.PubMedGoogle Scholar
  35. Halliwell, B., and Gutteridge, J. M., 1984, Oxygen toxicity, oxygen radicals, transition metals and disease, Biochem. J. 219(2): 557.Google Scholar
  36. Harakeh, S., and Jariwalla, R. J., 1991, Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV infected cells, Am. J. Clin. Nutr. 54:1231S.Google Scholar
  37. Harakeh, S., and Jariwalla, R. J., 1994, Comparative analysis of ascorbate and AZT effects on HIV production in persistently infected cell lines, J. Nutr. Med. 4:393–401.CrossRefGoogle Scholar
  38. Harakeh, S., Jariwalla, R. J., and Pauling, L., 1990, Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells, Proc. Natl. Acad. Sci. USA 87:7245.PubMedCrossRefGoogle Scholar
  39. Harakeh, S., Niedzwiecki, A., and Jariwalla, R. J., 1994, Mechanistic analysis of ascorbate inhibition of human immunodeficiency virus, Chem.-Biol. Interact. 91:207–215.PubMedCrossRefGoogle Scholar
  40. Haskell, B. E., and Johnston, C. S., 1991, Complement component C1q activity and ascorbic acid nutriture in guinea pigs, Am. J. Clin. Nutr. 54:1228S.PubMedGoogle Scholar
  41. Hemilä, H., 1992, Vitamin C and the common cold, Br. J. Nutr. 67:3-16.PubMedCrossRefGoogle Scholar
  42. Hemilä, H., 1994, Does vitamin C alleviate the symptoms of the common cold?—A review of current evidence, Scand. J. Infect. Dis. 26:1–6.PubMedCrossRefGoogle Scholar
  43. Jariwalla, R. J., and Harakeh, S., 1992, HIV suppression by ascorbate and its enhancement by a glutathione precursor, in Eighth International Conference on AIDS, Amsterdam, 2 B07.Google Scholar
  44. Jariwalla, R. J., and Harakeh, S., 1994, Ascorbic acid and AIDS: Strategic functions and therapeutic possibilities, in Nutrition and AIDS (R. Watson, ed.), pp. 117–139, CRC Press, Boca Raton.Google Scholar
  45. Joffe, M. I., Sukha, N. R., and Rabson, A. R., 1983, Lymphocyte subsets in measles. Depressed helper inducer subpopulation reversed by in vitro treatment with levamisole and ascorbic acid, J. Clin. Invest. 72:971.PubMedCrossRefGoogle Scholar
  46. Johnston, C. S., and Huang, S., 1991, Effect of ascorbic acid nutriture on blood histamine and neutrophil Chemotaxis in guinea pigs, J. Nutr. 121:126.PubMedGoogle Scholar
  47. Johnston, C. S., Kolb, W. P., and Haskell, B. E., 1985, The effect of vitamin C nutriture on complement component clq in guinea pig plasma, J. Nutr. 115: 1089.PubMedGoogle Scholar
  48. Johnston, C S., Carter, G. D., and Haskell, B. E., 1987, The effect of ascorbic acid nutriture on protein bound hydroproline in guinea pig plasma, J. Nutr. 117:764.PubMedGoogle Scholar
  49. Johnston, C. S., Martin, L. J., and Cai, X., 1992, Antihistamine effect of supplemental ascorbic acid and neutrophil Chemotaxis, J. Am. Coll. Nutr. 121:126–130.Google Scholar
  50. Jonas, E., Dwenger, A., and Hater, A., 1993, In vitro effect of ascorbic acid on neutrophil-endothelial cell interaction, J. Biolumin. Chemilumin. 8:15–20.PubMedCrossRefGoogle Scholar
  51. Kalden, J. R., and Guthy, E. A., 1972, Prolonged skin allograft survival in vitamin C deficient guinea pigs, Eur. Surg. Res. 4:114.PubMedCrossRefGoogle Scholar
  52. Karpinska, T., Kawecki, Z., and Kandefer-Szerszen, M., 1982, The influence of ultraviolet irradiation, L-ascorbic acid and calcium chloride on the induction of interferon on human embryo fibroblasts, Arch. Immunol. Ther. Exp. 30:33.Google Scholar
  53. Kazakov, S. A., Astashkina, T. G., Mamaev, S. V., and Vlassov, V. V., 1988, Site-specific cleavage of single-stranded DNA at unique sites by a copper-dependent redox reaction, Nature 335:186–188.PubMedCrossRefGoogle Scholar
  54. Kienner, F. R., 1971, Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology, J. Appl. Nutr. 23:61–88.Google Scholar
  55. Klenner, F. R., 1974, Significance of high daily intake of ascorbic acid in preventive medicine, J. Int. Acad. Prev. Med. 1:45–69.Google Scholar
  56. Maderazo, E. C, Woronick, C. L., and Albano, S. D., 1986, Neutrophil dysfunction in trauma: Inappropriate activation, deactivation, and probable autooxidative damage as a mechanism of neutrophil locomotory defect, J. Infect. Dis. 154:471–477.PubMedCrossRefGoogle Scholar
  57. Maeda, H., and Akaike, T., 1991, Oxygen free radicals as pathogenic molecules in viral diseases, Proc. Soc. Exp. Biol. Med. 198:721–727.PubMedGoogle Scholar
  58. Manzella, J. P., and Roberts, N. J., 1979, Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia, J. Immunol. 123:1940.PubMedGoogle Scholar
  59. McGee, M. P., and Myrick, Q. N., 1979, Phagocytosis-induced injury of normal and activated alveolar macrophages, Infect. Immun. 26:910–915.PubMedGoogle Scholar
  60. Morishige, F., and Murata, A., 1978, Vitamin C for prophylaxis of viral hepatitis B in transfused patients, J. Int. Acad. Preventive Med. 5:54–58.Google Scholar
  61. Mueller, P. S., and Kies, M. W., 1962, Suppression of tuberculin reaction in the scorbutic guinea pig, Nature 195:813.PubMedCrossRefGoogle Scholar
  62. Mueller, P. S., Kies, M. S., Alvord, E. C, and Shaw, C, 1962, Prevention of experimental allergic encephalomyelitis (EAE) by vitamin C deprivation, J. Exp. Med. 115:329.PubMedCrossRefGoogle Scholar
  63. Muggli, R., 1993, Vitamin C and phagocytes, in Nutrient Modulation of the Immune Response (S. Cunningham-Rundles, ed.), pp. 75–90, Marcel Dekker, Inc., New York.Google Scholar
  64. Murata, A., and Uike, M., 1976, Mechanism of inactivation of bacteriophage M52 containing single-stranded RNA by ascorbic acid, J. Nutr. Sci. Vitaminol. 22:347.PubMedGoogle Scholar
  65. Murata, A., and Kitagawa, K., 1973, Mechanism of inactivation of bacteriophage J1 by ascorbic acid, Agric. Biol. Chem. 37:1145–1151.CrossRefGoogle Scholar
  66. Oberritter, H., Glatthaar, B., Moser, U., and Schmidt, K. H., 1986, Effect of functional stimulation on ascorbate content in phagocytes under physiological and pathological conditions, Int. Arch. Allergy Appl. Immunol. 81:46-50.PubMedCrossRefGoogle Scholar
  67. Oh, C., and Nakano, K., 1989, Reversal by ascorbic acid of suppression by endogenous histamine of rat lymphocyte blastogenesis, J. Nutr. 118:639.Google Scholar
  68. Packer, J. E., Slater, T. F., and Willson, R. L., 1979, Direct observation of a free radical interaction between vitamin E and vitamin C, Nature 278:737.Google Scholar
  69. Panush, R. S., and Delafuente, J. C,. 1979, Modulation of certain immunologic responses by vitamin C, Int. J. Vitam. Nutr. Res. 19:179.Google Scholar
  70. Panush, R. S., Delafuente, J. C, Katz, P., and Johnson, J., 1982, Modulation of certain immunologic responses by vitamin C, in Vitamin C (A. Hanck, ed), p. 35, Huber, Vienna.Google Scholar
  71. Pauling, L., 1971a, Ascorbic acid and the common cold, Am. J. Clin. Nutr. 24:1294-1299.PubMedGoogle Scholar
  72. Pauling, L., 1971b, The significance of the evidence about ascorbic acid and the common cold, Proc. Natl. Acad. Sci. USA 68:2678-2681.PubMedCrossRefGoogle Scholar
  73. Pauling, L., 1986, How to Live Longer and Feel Better, W. H. Freeman and Co., New YorkGoogle Scholar
  74. Rebora, A., Dallegri, F., and Patrone, F., 1980, Neutrophil dysfunction and repeated infections: Influence of levamisole and ascorbic acid, Br. J. Dermatol. 102:49–56.PubMedCrossRefGoogle Scholar
  75. Reid, M. E., and Briggs, G. M., 1953, Development of semisynthetic diet for young guinea pigs, J. Nutr. 51:34.Google Scholar
  76. Ritzel, G., 1961, Critical analysis of the role of vitamin C in the treatment of the common cold [German], Helv. Med. Acta 28:63–68.PubMedGoogle Scholar
  77. Ritzel, G., 1976, Ascorbic acid and the common cold, J. Am. Med. Assoc. 235:1108.CrossRefGoogle Scholar
  78. Schmidt, K., and Moser, U., 1985, Vitamin C—A modulator of host defense mechanism, Int. J. Vitam. Nutr. Res. suppl. 27:363–379.PubMedGoogle Scholar
  79. Schwarz, R. I., 1991, Ascorbate stabilizes the differentiated state and reduces the ability of Rous sarcoma virus to replicate and to uniformly transform cell cultures, Am. J. Clin. Nutr. 54:1247S.PubMedGoogle Scholar
  80. Schwerdt, P. R., and Schwerdt, C. E., 1975, Effect of ascorbic acid on rhinovirus replication in WI-38 cells (38724), Proc. Soc. Exp. Biol. Med. 148:1237.PubMedGoogle Scholar
  81. Siegel, B. V., 1973, Enhanced interferon response to murine leukemia virus by ascorbic acid, Infect. Immun. 10:409.Google Scholar
  82. Siegel, B. V., 1975, Enhancement of interferon production by Poly (rl) Poly (rC) in mouse cultures by ascorbic acid, Nature, 254:531.PubMedCrossRefGoogle Scholar
  83. Siegel, B. V., and Morton, J. J., 1977, Vitamin C and the immune response, Experientia 33:393.PubMedCrossRefGoogle Scholar
  84. Smith, M. J. H., and Walker, J. R., 1980, The effect of some antirheumatic drugs on an in vitro model of human polymorphonuclear leukocyte chemokinesis, Br. J. Pharmacol. 69:473–478.PubMedGoogle Scholar
  85. Stone, I., 1972, The Healing Factor: Vitamin C against Disease, Grosset and Dunlap, New York.Google Scholar
  86. Thomas, W. B., and Holt, P. G., 1978, Vitamin C and immunity: An assessment of the evidence, Clin. Exp. Immunol. 32:370.PubMedGoogle Scholar
  87. Thorner, R. E., Barker, C. F, and MacGregor, R. R., 1983, Improvement of granulocyte adherence and in vivo granulocyte delivery by ascorbic acid in renal transplant patients, Transplantation 35:432–436.PubMedCrossRefGoogle Scholar
  88. Vogel, R. I., Lamster, I. B., Wechsler, S. A., Macedo, B., Hartley, L. J., and Macedo, J. A., 1986, The effects of megadoses of ascorbic acid on polymorphonuclear neutrophil Chemotaxis and experimental gingivitis, J. Periodontol. 51:412–419.Google Scholar
  89. Weitberg, A. D., 1987, Antioxidants inhibit the effect of vitamin C on oxygen radical induced sister chromatid exchanges, Mutat. Res. 191(1):53.PubMedCrossRefGoogle Scholar
  90. Yonemoto, R. H., 1979, in Vitamin C: Recent Advances and Aspects of Virus Diseases in Lipid Metabolism, (A. Hanck, ed.), p. 143, Huber, Vienna.Google Scholar
  91. Yonemoto, R. H., Chreitien, P. B., and Fehniger, T. F., 1976, Enhanced lymphocyte blastogenesis by oral ascorbic acid, Proc. Am. Assoc. Cancer Res. 17:288.Google Scholar
  92. Zweiman, B., Besdine, R. W., and Hildreth, E. A., 1966, The effect of the scorbutic state on tuberculin hypersensitivity in the guinea pig. II. In vitro mitotic response of lymphocytes, J. Immunol. 96:672.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Raxit J. Jariwalla
    • 1
  • Steve Harakeh
    • 1
  1. 1.Virology and Immunodeficiency Research ProgramLinus Pauling Institute of Science and MedicinePalo AltoUSA

Personalised recommendations