Abstract
The major physiological function of milk is the transport of amino acids, carbohydrates, lipids, and minerals to mammalian offspring. However, milk is also a rich collection of antimicrobial substances, which provide protection against pathogenic infections. These molecules safeguard the integrity of the lactating mammary gland, but also provide protection for the suckling offspring during a time when its immune system is still immature. The protective substances can be classified into two categories: 1) nonspecific defense substances, which provide innate immunity, and 2) molecules such as antibodies, which provide adaptive immunity and are directed against specific pathogens. The antimicrobial potency of milk has not been a target for farm animal breeding in the past, and present day ruminants provide suboptimal levels of antimicrobial substances in milk. Altered breeding regimes, pharmacological intervention, and transgenesis can be utilized to improve the antimicrobial properties of milk. Such alterations of milk composition have implications for human and animal health.
Keywords: milk, immunology, pathogen, protection, neutralization
REFERENCES
- 1.Lehrer R. I., Ganz T. Antimicrobial peptides in mammalian and insect host defence. Curr. Opin. Immunol. 1999;11:23–27. doi: 10.1016/s0952-7915(99)80005-3. [DOI] [PubMed] [Google Scholar]
- 2.Telemo E., Hanson L.A. Antibodies in milk. J. Mam. Gland Biol. Neoplasia. 1996;1:243–249. doi: 10.1007/BF02018077. [DOI] [PubMed] [Google Scholar]
- 3.Filipp D., Alizadeh-Khiavi K., Richardson C., Palma A., Paredes N., Takeuchi O., Akira S., Julius M. Sol-uble CD14 enriched in colostrum and milk induces B cell growth and differentiation. Proc. Natl. Acad. Sci. USA. 2001;98:603–608. doi: 10.1073/pnas.98.2.603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sordillo L. M., Shafer-Weaver K., de Rosa D. Im-munobiology of the mammarygland. J. Dairy Sci. 1997;80:1851–1865. doi: 10.3168/jds.S0022-0302(97)76121-6. [DOI] [PubMed] [Google Scholar]
- 5.Hanson L. A. The mother–offspring dyad and the im-mune system. Acta Paediatr. 2000;89:252–258. [PubMed] [Google Scholar]
- 6.Zhou L., Yoshimura Y., Huang Y. Y., Suzuki R., Yokoyama M., Okabe M., Shimamura M. Two independent path-ways of maternal cell transmission to offspring: Through pla-centa during pregnancy and by breast-feeding after birth. Immunology. 2000;101:570–580. doi: 10.1046/j.1365-2567.2000.00144.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Nuijens J. H., van Berkel P. H., Schanbacher F. L. Structure and biological actions of lactoferrin. J. Mam. Gland Biol. Neoplasia. 1996;1:285–295. doi: 10.1007/BF02018081. [DOI] [PubMed] [Google Scholar]
- 8.B. L. Larson (1992). Immunoglobulins of the mammary secre-tons. In P. F. Fox (ed.), Advanced Dairy Chemistry, Vol: 1 Pro-teins, Elsevier, London, pp. 231–254.
- 9.Hunziker W., Kraehenbuhl J. P. Epithelial transcyto-sis of immunoglobulins. J. Mam. Gland Biol. Neoplasia. 1998;3:287–302. doi: 10.1023/a:1018715511178. [DOI] [PubMed] [Google Scholar]
- 10.Butcher E. C., Picker L. J. Lymphocyte homing and homeostasis. Science. 1996;272:60–66. doi: 10.1126/science.272.5258.60. [DOI] [PubMed] [Google Scholar]
- 11.Johansen F. E., Braathen R., Brandtzaeg P. Role of J chain in secretory immunoglobulin formation. Scand. J. Immunol. 2000;52:240–248. doi: 10.1046/j.1365-3083.2000.00790.x. [DOI] [PubMed] [Google Scholar]
- 12.Johansen F. E., Pekna M., Norderhaug I. N., Haneberg B., Hietala M. A., Krajci P., Betsholtz C., Brandtzaeg P. Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglob-ulin receptor/secretory component-deficient mice. J. Exp. Med. 1999;190:915–922. doi: 10.1084/jem.190.7.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Barrington G. M., McFaden T. B., Huyler M. T., Besser T. E. Regulation of colostrogenesis in cattle. Livestock Prod. Sci. 2001;70:95–104. [Google Scholar]
- 14.Israel E. J., Patel V. K., Taylor S. F., Marshak-Rothstein A., Simister N. E. Requirement for a beta 2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice. J. Immunol. 1995;154:6246–6251. [PubMed] [Google Scholar]
- 15.Velin D., Acha-Orbea H., Kraehenbuhl J. P. The neonatal Fc receptor is not required for mucosal infection by mouse mammary tumor virus. J. Virol. 1996;70:7250–7254. doi: 10.1128/jvi.70.10.7250-7254.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Barrington G. M., Besser T. E., Davis W. C., Gay C. C., Reeves J. J., McFadden T. B. Expression of im-munoglobulin G1receptors by bovine mammaryepithelial cells and mammary leukocytes. J. Dairy Sci. 1997;80:86–93. doi: 10.3168/jds.S0022-0302(97)75915-0. [DOI] [PubMed] [Google Scholar]
- 17.Barrington G. M., Besser T. E., Gay C. C., Davis W. C., Reeves J. J., McFadden T. B. Effect of prolactin on in vitro expression of the bovine mammary immunoglobulin G1 receptor. J. Dairy Sci. 1997;80:94–100. doi: 10.3168/jds.S0022-0302(97)75916-2. [DOI] [PubMed] [Google Scholar]
- 18.Lamprecht C. L., Krause H. E., Mufson M. A. Role of maternal antibody in pneumonia and bronchiolitis due to respiratory syncytial virus. J. Infect. Dis. 1976;134:211–217. doi: 10.1093/infdis/134.3.211. [DOI] [PubMed] [Google Scholar]
- 19.Enjuanes L., van der Zeijst B. A. M. Molecular ba-sis of transmissible gastroenteritis virus epidemiology. In: Siddell S. G., editor. The Coronaviridae. New York: Plenum Press; 1995. pp. 337–376. [Google Scholar]
- 20.Jenkins M. C., O'Brien C., Trout J., Guidry A., Fayer R. Hyperimmune bovine colostrum specific for recombi-nant Cryptosporidium parvum antigen confers partial protec-tion against cryptosporidiosis in immunosuppressed adult mice. Vaccine. 1999;17:2453–2460. doi: 10.1016/s0264-410x(98)00369-7. [DOI] [PubMed] [Google Scholar]
- 21.Stephan W., Dichtelmuller H., Lissner R. Antibod-ies from colostrum in oral immunotherapy. J. Clin. Chem. Clin. Biochem. 1990;28:19–23. [PubMed] [Google Scholar]
- 22.H. Korhonen, P. Marnila, and H. S. Gill (2000). Milk im-munoglobulins and complement factors. Br.J.Nutr. S75–S80. [DOI] [PubMed]
- 23.H. Korhonen, P. Marnila, and H. S. Gill (2000). Bovine milk antibodies for health. Br.J.Nutr. S135–S146. [DOI] [PubMed]
- 24.Loimaranta V., Nuutila J., Marnila P., Tenovuo J., Korhonen H., Lilius E. M. Colostral proteins from cows immu-nised with Streptococcus mutans/S. sobrinus support the phago-cytosis and killing of mutans streptococci by human leucocytes. J. Med. Microbiol. 1999;48:917–926. doi: 10.1099/00222615-48-10-917. [DOI] [PubMed] [Google Scholar]
- 25.Okamoto Y., Tsutsumi H., Kumar N. S., Ogra P. L. Effect of breast feeding on the development of anti-idiotype antibody response to F glycoprotein of respiratory syncytial virus in infant mice after post-partum maternal immunization. J. Immunol. 1989;142:2507–2512. [PubMed] [Google Scholar]
- 26.Pollock D. P., Kutzko J. P., Birck-Wilson E., Williams, Y. Echelard J. L., Meade H. M. Transgenic milk as a method for the production of recombinant antibodies. J. Immunol. Methods. 1999;231:147–157. doi: 10.1016/S0022-1759(99)00151-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sola I., Castilla J., Pintado B., Sanchez-Morgado J. M., Whitelaw C. B., Clark A. J., Enjuanes L. Transgenic mice secreting coronavirus neutralizing antibodies into the milk. J. Virol. 1998;72:3762–3772. doi: 10.1128/jvi.72.5.3762-3772.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Zhang P., Sawicki V., Lewis A., Hanson L., Nuijens J. H., Neville M. C. Human lactoferrin in the milk of trans-genic mice increases intestinal growth in ten-day-old suckling neonates. Adv. Exp. Med. Biol. 2001;501:107–113. doi: 10.1007/978-1-4615-1371-1_13. [DOI] [PubMed] [Google Scholar]
- 29.Platenburg G. J., Kootwijk E. P., Kooiman P. M., Woloshuk S. L., Nuijens J. H., Krimpenfort P. J., Pieper F. R., de Boer H. A., Strijker R. Expression of human lactoferrin in milk of transgenic mice. Transgenic Res. 1994;3:99–108. doi: 10.1007/BF01974087. [DOI] [PubMed] [Google Scholar]
- 30.Kim S. J., Sohn B. H., Jeong S., Pak K. W., Park J. S., Park I. Y., Lee T. H., Choi Y. H., Lee C. S., Han Y. M., Yu D. Y., Lee K. K. High-level expression of human lactoferrin in milk of transgenic mice using genomic lactoferrin sequence. J. Biochem. (Tokyo) 1999;126:320–325. doi: 10.1093/oxfordjournals.jbchem.a022452. [DOI] [PubMed] [Google Scholar]
- 31.Yarus S., Rosen J. M., Cole A. M., Diamond G. Production of active bovine tracheal antimicrobial peptide in milk of transgenic mice. Proc. Natl. Acad. Sci. USA. 1996;93:14118–14121. doi: 10.1073/pnas.93.24.14118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Maga E. A., Anderson G. B., Murray J. D. The effect of mammary gland expression of human lysozyme on the properties of milk from transgenic mice. J. Dairy Sci. 1995;78:2645–2652. doi: 10.3168/jds.S0022-0302(95)76894-1. [DOI] [PubMed] [Google Scholar]
- 33.Maga E. A., Anderson G. B., Cullor J. S., Smith W., Murray J. D. Antimicrobial properties of human lysozyme transgenic mouse milk. J. Food Prot. 1998;61:52–56. doi: 10.4315/0362-028x-61.1.52. [DOI] [PubMed] [Google Scholar]
- 34.Kerr D. E., Plaut K., Bramley A. J., Williamson C. M., Lax A. J., Moore K., Wells K. D., Wall R. J. Lysostaphin ex-pression in mammary glands confers protection against staphy-lococcal infection in transgenic mice. Nat. Biotechnol. 2001;19:66–70. doi: 10.1038/83540. [DOI] [PubMed] [Google Scholar]
- 35.Kolb A. F., Pewe L., Webster J., Perlman S., Whitelaw C. B., Siddell S. G. Virus-neutralizing monoclonal antibody expressed in milk of transgenic mice provides full protection against virus-induced encephalitis. J. Virol. 2001;75:2803–2809. doi: 10.1128/JVI.75.6.2803-2809.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Clark A. J., Cowper A., Wallace R., Wright G., Simons J. P. Rescuing transgene expression by co-integration. Biotechnology. 1992;10:1450–1454. doi: 10.1038/nbt1192-1450. [DOI] [PubMed] [Google Scholar]
- 37.Dobie K. W., Lee M., Fantes J. A., Graham E., Clark A. J., Springbett A., Lathe R., McClenaghan M. Variegated transgene expression in mouse mammary gland is determined by the transgene integration locus. Proc. Natl. Acad. Sci. USA. 1996;93:6659–6664. doi: 10.1073/pnas.93.13.6659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Kolb A. F., Ansell R., McWhir J., Siddell S. G. In-sertion of a foreign gene into the beta-casein locus by Cre-mediated site-specific recombination. Gene. 1999;227:21–31. doi: 10.1016/s0378-1119(98)00607-6. [DOI] [PubMed] [Google Scholar]
- 39.Groot N. d., van Kuik-Romeijn P., Lee S. H., de Boer H. A. Increased immunoglobulin A levels in milk by over-expressing the murine polymeric immunoglobulin recep-tor gene in the mammary gland epithelial cells of transgenic mice. Immunology. 2000;101:218–224. doi: 10.1046/j.1365-2567.2000.00094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Furth P. A. Conditional control of gene expression in the mammary gland. J. Mam. Gland Biol. Neoplasia. 1997;2:373–383. doi: 10.1023/a:1026399329934. [DOI] [PubMed] [Google Scholar]
- 41.Soulier S., Stinnakre M. G., Lepourry L., Mercier J. C., Vilotte J. L. Use of doxycycline-controlled gene expression to reversibly alter milk-protein composition in transgenic mice. Eur. J. Biochem. 1999;260:533–539. doi: 10.1046/j.1432-1327.1999.00200.x. [DOI] [PubMed] [Google Scholar]
- 42.Jakobovits A. Production of fully human antibodies by transgenic mice. Curr. Opin. Biotechnol. 1995;6:561–566. doi: 10.1016/0958-1669(95)80093-x. [DOI] [PubMed] [Google Scholar]
- 43.Tomizuka K., Shinohara T., Yoshida H., Uejima H., Ohguma A., Tanaka S., Sato K., Oshimura M., Ishida I. Double trans-chromosomic mice: Maintenance of two individ-ual human chromosome fragments containing Ig heavy and kappa loci and expression of fully human antibodies. Proc. Natl. Acad. Sci. USA. 2000;97:722–727. doi: 10.1073/pnas.97.2.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Jakobovits A. Production and selection of antigen-specific fully human monoclonal antibodies from mice engi-neered with human Ig loci. Adv. Drug Deliv. Rev. 1998;31:33–42. doi: 10.1016/s0169-409x(97)00092-6. [DOI] [PubMed] [Google Scholar]
- 45.Newburg D. S. Oligosaccharides and glycoconjugates in human milk: Their role in host defense. J. Mam. Gland Biol. Neoplasia. 1996;1:271–283. doi: 10.1007/BF02018080. [DOI] [PubMed] [Google Scholar]
- 46.Goldman A. S., Chheda S., Garofalo R., Schmalstieg F. C. Cytokines in human milk: Properties and potential ef-fects upon the mammary gland and the neonate. J. Mam. Gland Biol. Neoplasia. 1996;1:251–258. doi: 10.1007/BF02018078. [DOI] [PubMed] [Google Scholar]
- 47.Hwang P. M., Zhou N., Shan X., Arrowsmith C. H., Vogel H. J. Three-dimensional solution structure of lacto-ferricin B, an antimicrobial peptide derived from bovine lacto-ferrin. Biochemistry. 1998;37:4288–4298. doi: 10.1021/bi972323m. [DOI] [PubMed] [Google Scholar]
- 48.Baveye S., Elass E., Mazurier J., Spik G., Legrand D. Lactoferrin: A multifunctional glycoprotein involved in the modulation of the inflammatory process. Clin. Chem. Lab. Med. 1999;37:281–286. doi: 10.1515/CCLM.1999.049. [DOI] [PubMed] [Google Scholar]
- 49.van der Strate B. W., Beljaars L., Molema G., Harmsen M. C., Meijer D. K. Antiviral activities of lactoferrin. An-tiviral Res. 2001;52:225–239. doi: 10.1016/s0166-3542(01)00195-4. [DOI] [PubMed] [Google Scholar]
- 50.Valenti P., Greco R., Pitari G., Rossi P., Ajello M., Melino G., Antonini G. Apoptosis of Caco-2 intestinal cells invaded by Listeria monocytogenes: Protective effect of lacto-ferrin. Exp. Cell Res. 1999;250:197–202. doi: 10.1006/excr.1999.4500. [DOI] [PubMed] [Google Scholar]
- 51.Wada T., Aiba Y., Shimizu K., Takagi A., Miwa T., Koga Y. The therapeutic effect of bovine lactoferrin in the host infected with Helicobacter pylori. Scand. J. Gastroenterol. 1999;34:238–243. doi: 10.1080/00365529950173627. [DOI] [PubMed] [Google Scholar]
- 52.Hanson L. A. Breastfeeding provides passive and likely long-lasting active immunity. Ann. Allergy Asthma Immunol. 1998;81:523–533. doi: 10.1016/S1081-1206(10)62704-4. [DOI] [PubMed] [Google Scholar]
- 53.Kolb A. F. The prospects of modifying the antimicrobial properties of milk. Biotechn. Adv. 2001;19:299–316. doi: 10.1016/S0734-9750(01)00069-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Edde L., Hipolito R. B., Hwang F. F., Headon D. R., Shalwitz R. A., Sherman M. P. Lactoferrin protects neonatal rats from gut-related systemic infection. Am. J. Phys-iol. Gastrointest. Liver Physiol. 2001;281:G1140–G1150. doi: 10.1152/ajpgi.2001.281.5.G1140. [DOI] [PubMed] [Google Scholar]
- 55.Hanson L. H., Sawicki V., Lewis A., Nuijens J. H., Neville M. C., Zhang P. Does human lactoferrin in the milk of transgenic mice deliver iron to suckling neonates? Adv. Exp. Med. Biol. 2001;501:233–239. doi: 10.1007/978-1-4615-1371-1_29. [DOI] [PubMed] [Google Scholar]
- 56.Krimpenfort P., Rademakers A., Eyestone W., van der Schans A., van den Broek S., Kooiman P., Kootwijk E., Platenburg G., Pieper F., Strijker R., de Boer H. A. Generation of transgenic dairy cattle using ‘in vitro’ embryo production. Biotechnology (NY) 1991;9:844–847. doi: 10.1038/nbt0991-844. [DOI] [PubMed] [Google Scholar]
- 57.Hwang P. M., Vogel H. J. Structure–function rela-tionships of antimicrobial peptides. Biochem. Cell Biol. 1998;76:235–246. doi: 10.1139/bcb-76-2-3-235. [DOI] [PubMed] [Google Scholar]
- 58.Bellamy W., Takase M., Wakabayashi H., Kawase K., Tomita M. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J. Appl. Bacteriol. 1992;73:472–479. doi: 10.1111/j.1365-2672.1992.tb05007.x. [DOI] [PubMed] [Google Scholar]
- 59.Ulvatne H., Haukland H. H., Olsvik O., Vorland L. H. Lactoferricin B causes depolarization of the cytoplas-mic membrane of Escherichia coli ATCC 25922 and fusion of negatively charged liposomes. FEBS Lett. 2001;492:62–65. doi: 10.1016/s0014-5793(01)02233-5. [DOI] [PubMed] [Google Scholar]
- 60.Drews R., Paleyanda R. K., Lee T. K., Chang R. R., Rehemtulla A., Kaufman R. J., Drohan W. N., Lubon H. Proteolytic maturation of protein C upon engineering the mouse mammary gland to express furin. Proc. Natl. Acad. Sci. USA. 1995;92:10462–10466. doi: 10.1073/pnas.92.23.10462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Zucht H. D., Raida M., Adermann K., Magert H. J., Forssmann W. G. Casocidin-I: Acasein-alpha s2 derived peptide exhibits antibacterial activity. FEBS Lett. 1995;372:185–188. doi: 10.1016/0014-5793(95)00974-e. [DOI] [PubMed] [Google Scholar]
- 62.Recio I., Visser S. Identification of two distinct an-tibacterial domains within the sequence of bovine alpha(s2)-casein. Biochim. Biophys. Acta. 1999;1428:314–326. doi: 10.1016/s0304-4165(99)00079-3. [DOI] [PubMed] [Google Scholar]
- 63.Pellegrini A., Thomas U., Bramaz N., Hunziker P., von Fellenberg R. Isolation and identification of three bac-tericidal domains in the bovine alpha-lactalbumin molecule. Biochim. Biophys. Acta. 1999;1426:439–448. doi: 10.1016/s0304-4165(98)00165-2. [DOI] [PubMed] [Google Scholar]
- 64.Lahov E., Regelson W. Antibacterial and immuno-stimulating casein-derived substances from milk: Casecidin, is-racidin peptides. Food Chem. Toxicol. 1996;34:131–145. doi: 10.1016/0278-6915(95)00097-6. [DOI] [PubMed] [Google Scholar]
- 65.Jia H. P., Starner T., Ackermann M., Kirby P., Tack B. F., McCray P. B. J. Abundant human beta-defensin-1 ex-pression in milk and mammary gland epithelium. J. Pediatr. 2000;138:109–112. doi: 10.1067/mpd.2001.109375. [DOI] [PubMed] [Google Scholar]
- 66.Tossi A., Tarantino C., Romeo D. Design of syn-thetic antimicrobial peptides based on sequence analogy and amphipathicity. Eur. J. Biochem. 1997;250:549–558. doi: 10.1111/j.1432-1033.1997.0549a.x. [DOI] [PubMed] [Google Scholar]
- 67.Tzou P., de Gregorio E., Lemaitre B. How Drosophila combats microbial infection: A model to study in-nate immunity and host–pathogen interactions. Curr. Opin. Microbiol. 2002;5:102–110. doi: 10.1016/s1369-5274(02)00294-1. [DOI] [PubMed] [Google Scholar]
- 68.Schutte B. C., Mitros J. P., Bartlett J. A., Walters J. D., Jia H. P., Welsh M. J., Casavant T. L., J. McCray P. B. Discovery of five conserved beta-defensin gene clusters using a computational search strategy. Proc. Natl. Acad. Sci. USA. 2002;99:2129–2133. doi: 10.1073/pnas.042692699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Hamosh M. Protective function of proteins and lipids in human milk. Biol. Neonate. 1998;74:163–176. doi: 10.1159/000014021. [DOI] [PubMed] [Google Scholar]
- 70.K. D. Kussendrager and A. C. van Hooijdonk (2000). Lactoper-oxidase: Physico-chemical properties, occurrence, mechanism of action and applications. Br.J.Nutr. S19–S25. [DOI] [PubMed]