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. 1992 Nov;90(5):1984–1991. doi: 10.1172/JCI116078

Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis.

R H Yolken 1, J A Peterson 1, S L Vonderfecht 1, E T Fouts 1, K Midthun 1, D S Newburg 1
PMCID: PMC443262  PMID: 1331178

Abstract

Acute gastrointestinal infections due to rotaviruses and other enteric pathogens are major causes of morbidity and mortality in infants and young children throughout the world. Breast-feeding can reduce the rate of serious gastroenteritis in infants; however, the degrees of protection offered against rotavirus infection vary in different populations. The mechanisms associated with milk-mediated protection against viral gastroenteritis have not been fully elucidated. We have isolated a macromolecular component of human milk that inhibits the replication of rotaviruses in tissue culture and prevents the development of gastroenteritis in an animal model system. Purification of the component indicates that the antiviral activity is associated with an acidic fraction (pI = 4.0-4.6), which is free of detectable immunoglobulins. Furthermore, high levels of antiviral activity are associated with an affinity-purified complex of human milk mucin. Deglycosylation of the mucin complex results in the loss of antiviral activity. Further purification indicated that rotavirus specifically binds to the milk mucin complex as well as to the 46-kD glycoprotein component of the complex. Binding to the 46-kD component was substantially reduced after chemical hydrolysis of sialic acid. We have documented that human milk mucin can bind to rotavirus and inhibit viral replication in vitro and in vivo. Variations in milk mucin glycoproteins may be associated with different levels of protection against infection with gastrointestinal pathogens.

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Selected References

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  1. Bass D. M., Mackow E. R., Greenberg H. B. Identification and partial characterization of a rhesus rotavirus binding glycoprotein on murine enterocytes. Virology. 1991 Aug;183(2):602–610. doi: 10.1016/0042-6822(91)90989-o. [DOI] [PubMed] [Google Scholar]
  2. Berger R., Hadziselimovic F., Just M., Reigel F. Influence of breast milk on nosocomial rotavirus infections in infants. Infection. 1984 May-Jun;12(3):171–174. doi: 10.1007/BF01640892. [DOI] [PubMed] [Google Scholar]
  3. Bernstein D. I., Smith V. E., Sander D. S., Pax K. A., Schiff G. M., Ward R. L. Evaluation of WC3 rotavirus vaccine and correlates of protection in healthy infants. J Infect Dis. 1990 Nov;162(5):1055–1062. doi: 10.1093/infdis/162.5.1055. [DOI] [PubMed] [Google Scholar]
  4. Blacklow N. R., Greenberg H. B. Viral gastroenteritis. N Engl J Med. 1991 Jul 25;325(4):252–264. doi: 10.1056/NEJM199107253250406. [DOI] [PubMed] [Google Scholar]
  5. Clark H. F., Borian F. E., Bell L. M., Modesto K., Gouvea V., Plotkin S. A. Protective effect of WC3 vaccine against rotavirus diarrhea in infants during a predominantly serotype 1 rotavirus season. J Infect Dis. 1988 Sep;158(3):570–587. doi: 10.1093/infdis/158.3.570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cunningham A. S. Breast-feeding and health. J Pediatr. 1987 Apr;110(4):658–659. doi: 10.1016/s0022-3476(87)80574-7. [DOI] [PubMed] [Google Scholar]
  7. Duffy L. C., Riepenhoff-Talty M., Byers T. E., La Scolea L. J., Zielezny M. A., Dryja D. M., Ogra P. L. Modulation of rotavirus enteritis during breast-feeding. Implications on alterations in the intestinal bacterial flora. Am J Dis Child. 1986 Nov;140(11):1164–1168. doi: 10.1001/archpedi.1986.02140250090041. [DOI] [PubMed] [Google Scholar]
  8. Duwe A. K., Ceriani R. L. Human milk-fat globule membrane derived mucin is a disulfide-linked heteromer. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1305–1311. doi: 10.1016/0006-291x(89)92745-9. [DOI] [PubMed] [Google Scholar]
  9. Fukudome K., Yoshie O., Konno T. Comparison of human, simian, and bovine rotaviruses for requirement of sialic acid in hemagglutination and cell adsorption. Virology. 1989 Sep;172(1):196–205. doi: 10.1016/0042-6822(89)90121-9. [DOI] [PubMed] [Google Scholar]
  10. GIBBONS R. A. THE SENSITIVITY OF THE NEURAMINOSIDIC LINKAGE IN MUCOSUBSTANCES TOWARDS ACID AND TOWARDS NEURAMINIDASE. Biochem J. 1963 Nov;89:380–391. doi: 10.1042/bj0890380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Glass R. I., Stoll B. J. The protective effect of human milk against diarrhea. A review of studies from Bangladesh. Acta Paediatr Scand Suppl. 1989;351:131–136. doi: 10.1111/j.1651-2227.1989.tb11225.x. [DOI] [PubMed] [Google Scholar]
  12. Goldman A. S., Goldblum R. M. Human milk: immunologic-nutritional relationships. Ann N Y Acad Sci. 1990;587:236–245. doi: 10.1111/j.1749-6632.1990.tb00151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gothefors L., Wadell G., Juto P., Taniguchi K., Kapikian A. Z., Glass R. I. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis. 1989 Apr;159(4):753–757. doi: 10.1093/infdis/159.4.753. [DOI] [PubMed] [Google Scholar]
  14. Guerrant R. L., Hughes J. M., Lima N. L., Crane J. Diarrhea in developed and developing countries: magnitude, special settings, and etiologies. Rev Infect Dis. 1990 Jan-Feb;12 (Suppl 1):S41–S50. doi: 10.1093/clinids/12.Supplement_1.S41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gurwith M., Wenman W., Gurwith D., Brunton J., Feltham S., Greenberg H. Diarrhea among infants and young children in Canada: a longitudinal study in three northern communities. J Infect Dis. 1983 Apr;147(4):685–692. doi: 10.1093/infdis/147.4.685. [DOI] [PubMed] [Google Scholar]
  16. Gyorky G., Houck J. C. The determination of terminal protein-bound fucose. Can J Biochem. 1965 Nov;43(11):1807–1811. doi: 10.1139/o65-201. [DOI] [PubMed] [Google Scholar]
  17. Halvorsrud J., Orstavik I. An epidemic of rotavirus-associated gastroenteritis in a nursing home for the elderly. Scand J Infect Dis. 1980;12(3):161–164. doi: 10.3109/inf.1980.12.issue-3.01. [DOI] [PubMed] [Google Scholar]
  18. Ho M. S., Glass R. I., Pinsky P. F., Anderson L. J. Rotavirus as a cause of diarrheal morbidity and mortality in the United States. J Infect Dis. 1988 Nov;158(5):1112–1116. doi: 10.1093/infdis/158.5.1112. [DOI] [PubMed] [Google Scholar]
  19. Ho M. S., Glass R. I., Pinsky P. F., Young-Okoh N. C., Sappenfield W. M., Buehler J. W., Gunter N., Anderson L. J. Diarrheal deaths in American children. Are they preventable? JAMA. 1988 Dec 9;260(22):3281–3285. [PubMed] [Google Scholar]
  20. Hoshino Y., Wyatt R. G., Greenberg H. B., Flores J., Kapikian A. Z. Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque-reduction neutralization. J Infect Dis. 1984 May;149(5):694–702. doi: 10.1093/infdis/149.5.694. [DOI] [PubMed] [Google Scholar]
  21. Howie P. W., Forsyth J. S., Ogston S. A., Clark A., Florey C. D. Protective effect of breast feeding against infection. BMJ. 1990 Jan 6;300(6716):11–16. doi: 10.1136/bmj.300.6716.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Isaacs C. E., Kashyap S., Heird W. C., Thormar H. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child. 1990 Aug;65(8):861–864. doi: 10.1136/adc.65.8.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jason J. M., Nieburg P., Marks J. S. Mortality and infectious disease associated with infant-feeding practices in developing countries. Pediatrics. 1984 Oct;74(4 Pt 2):702–727. [PubMed] [Google Scholar]
  24. Jayashree S., Bhan M. K., Kumar R., Bhandari N., Sazawal S. Protection against neonatal rotavirus infection by breast milk antibodies and trypsin inhibitors. J Med Virol. 1988 Nov;26(3):333–338. doi: 10.1002/jmv.1890260313. [DOI] [PubMed] [Google Scholar]
  25. Jourdian G. W., Dean L., Roseman S. The sialic acids. XI. A periodate-resorcinol method for the quantitative estimation of free sialic acids and their glycosides. J Biol Chem. 1971 Jan 25;246(2):430–435. [PubMed] [Google Scholar]
  26. Laegreid A., Kolstø Otnaess A. B., Orstavik I., Carlsen K. H. Neutralizing activity in human milk fractions against respiratory syncytial virus. Acta Paediatr Scand. 1986 Sep;75(5):696–701. doi: 10.1111/j.1651-2227.1986.tb10276.x. [DOI] [PubMed] [Google Scholar]
  27. Lambert D. M. Role of oligosaccharides in the structure and function of respiratory syncytial virus glycoproteins. Virology. 1988 Jun;164(2):458–466. doi: 10.1016/0042-6822(88)90560-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Larocca D., Peterson J. A., Urrea R., Kuniyoshi J., Bistrain A. M., Ceriani R. L. A Mr 46,000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res. 1991 Sep 15;51(18):4994–4998. [PubMed] [Google Scholar]
  29. Larocca D., Peterson J. A., Walkup G., Urrea R., Ceriani R. L. Cloning and sequencing of a complementary DNA encoding a Mr 70,000 human breast epithelial mucin-associated antigen. Cancer Res. 1990 Sep 15;50(18):5925–5930. [PubMed] [Google Scholar]
  30. Lucas A., Cole T. J. Breast milk and neonatal necrotising enterocolitis. Lancet. 1990 Dec 22;336(8730):1519–1523. doi: 10.1016/0140-6736(90)93304-8. [DOI] [PubMed] [Google Scholar]
  31. Marrie T. J., Lee S. H., Faulkner R. S., Ethier J., Young C. H. Rotavirus infection in a geriatric population. Arch Intern Med. 1982 Feb;142(2):313–316. [PubMed] [Google Scholar]
  32. Mata L. J., Kronmal R. A., García B., Butler W., Urrutia J. J., Murillo S. Breast-feeding, weaning and the diarrhoeal syndrome in a Guatemalan Indian village. Ciba Found Symp. 1976;(42):311–338. doi: 10.1002/9780470720240.ch17. [DOI] [PubMed] [Google Scholar]
  33. Neuberger A., Ratcliffe W. A. The acid and enzymic hydrolysis of O-acetylated sialic acid residues from rabbit Tamm-Horsfall glycoprotein. Biochem J. 1972 Sep;129(3):683–693. doi: 10.1042/bj1290683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Newburg D. S., Pickering L. K., McCluer R. H., Cleary T. G. Fucosylated oligosaccharides of human milk protect suckling mice from heat-stabile enterotoxin of Escherichia coli. J Infect Dis. 1990 Nov;162(5):1075–1080. doi: 10.1093/infdis/162.5.1075. [DOI] [PubMed] [Google Scholar]
  35. Newburg D. S., Viscidi R. P., Ruff A., Yolken R. H. A human milk factor inhibits binding of human immunodeficiency virus to the CD4 receptor. Pediatr Res. 1992 Jan;31(1):22–28. doi: 10.1203/00006450-199201000-00004. [DOI] [PubMed] [Google Scholar]
  36. Okamoto Y., Ogra P. L. Antiviral factors in human milk: implications in respiratory syncytial virus infection. Acta Paediatr Scand Suppl. 1989;351:137–143. doi: 10.1111/j.1651-2227.1989.tb11226.x. [DOI] [PubMed] [Google Scholar]
  37. Patton S., Huston G. E., Jenness R., Vaucher Y. Differences between individuals in high-molecular weight glycoproteins from mammary epithelia of several species. Biochim Biophys Acta. 1989 Apr 28;980(3):333–338. doi: 10.1016/0005-2736(89)90321-0. [DOI] [PubMed] [Google Scholar]
  38. Peterson J. A., Zava D. T., Duwe A. K., Blank E. W., Battifora H., Ceriani R. L. Biochemical and histological characterization of antigens preferentially expressed on the surface and cytoplasm of breast carcinoma cells identified by monoclonal antibodies against the human milk fat globule. Hybridoma. 1990 Jun;9(3):221–235. doi: 10.1089/hyb.1990.9.221. [DOI] [PubMed] [Google Scholar]
  39. Pickering L. K., Evans D. G., DuPont H. L., Vollet J. J., 3rd, Evans D. J., Jr Diarrhea caused by Shigella, rotavirus, and Giardia in day-care centers: prospective study. J Pediatr. 1981 Jul;99(1):51–56. doi: 10.1016/s0022-3476(81)80956-0. [DOI] [PubMed] [Google Scholar]
  40. Rodriguez W. J., Kim H. W., Brandt C. D., Schwartz R. H., Gardner M. K., Jeffries B., Parrott R. H., Kaslow R. A., Smith J. I., Kapikian A. Z. Longitudinal study of rotavirus infection and gastroenteritis in families served by a pediatric medical practice: clinical and epidemiologic observations. Pediatr Infect Dis J. 1987 Feb;6(2):170–176. doi: 10.1097/00006454-198702000-00006. [DOI] [PubMed] [Google Scholar]
  41. Santosham M., Letson G. W., Wolff M., Reid R., Gahagan S., Adams R., Callahan C., Sack R. B., Kapikian A. Z. A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population. J Infect Dis. 1991 Mar;163(3):483–487. doi: 10.1093/infdis/163.3.483. [DOI] [PubMed] [Google Scholar]
  42. Saulsbury F. T., Winkelstein J. A., Yolken R. H. Chronic rotavirus infection in immunodeficiency. J Pediatr. 1980 Jul;97(1):61–65. doi: 10.1016/s0022-3476(80)80131-4. [DOI] [PubMed] [Google Scholar]
  43. Schauer R., Corfield A. P., Wember M., Danon D. A micro-method for quantitative determination of acylneuraminic acids from erythrocyte membranes. Hoppe Seylers Z Physiol Chem. 1975 Nov;356(11):1727–1732. doi: 10.1515/bchm2.1975.356.2.1727. [DOI] [PubMed] [Google Scholar]
  44. Shimizu M., Yamauchi K., Miyauchi Y., Sakurai T., Tokugawa K., McIlhinney R. A. High-Mr glycoprotein profiles in human milk serum and fat-globule membrane. Biochem J. 1986 Feb 1;233(3):725–730. doi: 10.1042/bj2330725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Snyder J. D., Merson M. H. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull World Health Organ. 1982;60(4):605–613. [PMC free article] [PubMed] [Google Scholar]
  46. Totterdell B. M., Nicholson K. G., MacLeod J., Chrystie I. L., Banatvala J. E. Neonatal rotavirus infection: role of lacteal neutralising alpha1-anti-trypsin and nonimmunoglobulin antiviral activity in protection. J Med Virol. 1982;10(1):37–44. doi: 10.1002/jmv.1890100106. [DOI] [PubMed] [Google Scholar]
  47. Vonderfecht S. L., Miskuff R. L., Wee S. B., Sato S., Tidwell R. R., Geratz J. D., Yolken R. H. Protease inhibitors suppress the in vitro and in vivo replication of rotavirus. J Clin Invest. 1988 Dec;82(6):2011–2016. doi: 10.1172/JCI113821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. WARREN L. The thiobarbituric acid assay of sialic acids. J Biol Chem. 1959 Aug;234(8):1971–1975. [PubMed] [Google Scholar]
  49. Weinberg R. J., Tipton G., Klish W. J., Brown M. R. Effect of breast-feeding on morbidity in rotavirus gastroenteritis. Pediatrics. 1984 Aug;74(2):250–253. [PubMed] [Google Scholar]
  50. Wertz G. W., Krieger M., Ball L. A. Structure and cell surface maturation of the attachment glycoprotein of human respiratory syncytial virus in a cell line deficient in O glycosylation. J Virol. 1989 Nov;63(11):4767–4776. doi: 10.1128/jvi.63.11.4767-4776.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Willoughby R. E., Yolken R. H. SA11 rotavirus is specifically inhibited by an acetylated sialic acid. J Infect Dis. 1990 Jan;161(1):116–119. doi: 10.1093/infdis/161.1.116. [DOI] [PubMed] [Google Scholar]
  52. Willoughby R. E., Yolken R. H., Schnaar R. L. Rotaviruses specifically bind to the neutral glycosphingolipid asialo-GM1. J Virol. 1990 Oct;64(10):4830–4835. doi: 10.1128/jvi.64.10.4830-4835.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wreschner D. H., Hareuveni M., Tsarfaty I., Smorodinsky N., Horev J., Zaretsky J., Kotkes P., Weiss M., Lathe R., Dion A. Human epithelial tumor antigen cDNA sequences. Differential splicing may generate multiple protein forms. Eur J Biochem. 1990 May 20;189(3):463–473. doi: 10.1111/j.1432-1033.1990.tb15511.x. [DOI] [PubMed] [Google Scholar]
  54. Yolken R. H., Bishop C. A., Townsend T. R., Bolyard E. A., Bartlett J., Santos G. W., Saral R. Infectious gastroenteritis in bone-marrow-transplant recipients. N Engl J Med. 1982 Apr 29;306(17):1010–1012. doi: 10.1056/NEJM198204293061701. [DOI] [PubMed] [Google Scholar]
  55. Yolken R. H., Willoughby R., Wee S. B., Miskuff R., Vonderfecht S. Sialic acid glycoproteins inhibit in vitro and in vivo replication of rotaviruses. J Clin Invest. 1987 Jan;79(1):148–154. doi: 10.1172/JCI112775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yolken R. H., Wyatt R. G., Mata L., Urrutia J. J., Garciá B., Chanock R. M., Kapikian A. Z. Secretory antibody directed against rotavirus in human milk--measurement by means of enzyme-linked immunosorbent assay. J Pediatr. 1978 Dec;93(6):916–921. doi: 10.1016/s0022-3476(78)81211-6. [DOI] [PubMed] [Google Scholar]

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