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Host-defence-related proteins in cows’ milk

Published online by Cambridge University Press:  11 November 2011

T. T. Wheeler ,
G. A. Smolenski ,
D. P. Harris ,
S. K. Gupta ,
B. J. Haigh ,
M. K. Broadhurst ,
A. J. Molenaar  and
K. Stelwagen
T. T. Wheeler*
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
G. A. Smolenski
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
D. P. Harris
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
S. K. Gupta
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
B. J. Haigh
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
M. K. Broadhurst
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
A. J. Molenaar
Affiliation:
Food and Bio-based Products Group, AgResearch Ltd, Ruakura Research Centre, Private Bag 3123, Hamilton 3214, New Zealand
K. Stelwagen
Affiliation:
SciLactis Ltd, Waikato Innovation Park, Ruakura Road, Hamilton 3240, New Zealand
*
†E-mail: tom.wheeler@agresearch.co.nz
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Abstract

Milk is a source of bioactive molecules with wide-ranging functions. Among these, the immune properties have been the best characterised. In recent years, it has become apparent that besides the immunoglobulins, milk also contains a range of minor immune-related proteins that collectively form a significant first line of defence against pathogens, acting both within the mammary gland itself as well as in the digestive tract of the suckling neonate. We have used proteomics technologies to characterise the repertoire of host-defence-related milk proteins in detail, revealing more than 100 distinct gene products in milk, of which at least 15 are known host-defence-related proteins. Those having intrinsic antimicrobial activity likely function as effector proteins of the local mucosal immune defence (e.g. defensins, cathelicidins and the calgranulins). Here, we focus on the activities and biological roles of the cathelicidins and mammary serum amyloid A. The function of the immune-related milk proteins that do not have intrinsic antimicrobial activity is also discussed, notably lipopolysaccharide-binding protein, RNase4, RNase5/angiogenin and cartilage-glycoprotein 39 kDa. Evidence is shown that at least some of these facilitate recognition of microbes, resulting in the activation of innate immune signalling pathways in cells associated with the mammary and/or gut mucosal surface. Finally, the contribution of the bacteria in milk to its functionality is discussed. These investigations are elucidating how an effective first line of defence is achieved in the bovine mammary gland and how milk contributes to optimal digestive function in the suckling calf. This study will contribute to a better understanding of the health benefits of milk, as well as to the development of high-value ingredients from milk.

Keywords

bovinemilkantimicrobialinnate immunity

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References

Affolter, M, Grass, L, Vanrobaeys, F, Casado, B, Kussmann, M 2010. Qualitative and quantitative profiling of the bovine milk fat globule membrane proteome. Journal of Proteomics 73, 1079–1088.Google Scholar
Ausubel, FM, Brent, R, Kingston, RE, Moore, D, Seidman, JG, Smith, JA, Struel, JA 1995. Current protocols in molecular biology. John Wiley & Sons, New York, NY, USA.Google Scholar
Bigg, HF, Wait, R, Rowan, AD, Cawston, TE 2006. The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation. Journal of Biological Chemistry 281, 21082–21095.CrossRefGoogle ScholarPubMed
Blackburn, D, Hayssen, V, Murphy, C 1989. The origin of lactation and the evolution of milk: a review with a new hypothesis. Mammal Reviews 19, 1–26.Google Scholar
Boix, E, Nogues, MV 2007. Mammalian antimicrobial proteins and peptides: overview on the RNase A superfamily members involved in innate host defence. Molecular Biosystems 3, 317–335.CrossRefGoogle ScholarPubMed
Clare, DA, Swaisgood, HE 2000. Bioactive milk peptides: a prospectus. Journal of Dairy Science 83, 1187–1195.CrossRefGoogle ScholarPubMed
Clare, DA, Catignani, GL, Swaisgood, HE 2003. Biodefense properties of milk: the role of antimicrobial proteins and peptides. Current Pharmaceutical Desisgn 9, 1239–1255.CrossRefGoogle ScholarPubMed
Dyer, KD, Rosenberg, HF 2006. The RNase a superfamily: generation of diversity and innate host defense. Molecular Diversity 10, 585–597.Google Scholar
Eckersall, PD, Young, FJ, McComb, C, Hogarth, CJ, Safi, S, Weber, A, McDonald, T, Nolan, AM, Fitzpatrick, JL 2001. Acute phase proteins in serum and milk from dairy cows with clinical mastitis. Veterinary Record 148, 35–41.CrossRefGoogle ScholarPubMed
Elias, JA, Homer, RJ, Hamid, Q, Lee, CG 2005. Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. Journal of Allergy and Clinical Immunology 116, 497–500.Google Scholar
Fett, JW, Strydom, DJ, Lobb, RR, Alderman, EM, Bethune, JL, Riordan, JF, Vallee, BL 1985. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24, 5480–5486.CrossRefGoogle ScholarPubMed
Flynn, A 1992. Minerals and trace elements in milk. Advances in Food and Nutrition Research 36, 209–252.CrossRefGoogle ScholarPubMed
Goldman, AS 2002. Evolution of the mammary gland defense system and the ontogeny of the immune system. Journal of Mammary Gland Biology and Neoplasia 7, 277–289.CrossRefGoogle ScholarPubMed
Goldman, AS, Chheda, S, Garofalo, R, Schmalstieg, FC 1996. Cytokines in human milk: properties and potential effects upon the mammary gland and the neonate. Journal of Mammary Gland Biology and Neoplasia 1, 251–258.CrossRefGoogle ScholarPubMed
Goldammer, T, Zerbe, H, Molenaar, A, Schuberth, HJ, Brunner, RM, Kata, SR, Seyfert, HM 2004. Mastitis increases mammary mRNA abundance of beta-defensin 5, toll-like-receptor 2 (TLR2), and TLR4 but not TLR9 in cattle. Clinical and Diagnostic Laboratory Immunology 11, 174–185.Google Scholar
Gronlund, U, Hulten, C, Eckersall, PD, Hogarth, C, Persson, WK 2003. Haptoglobin and serum amyloid A in milk and serum during acute and chronic experimentally induced Staphylococcus aureus mastitis. Journal of Dairy Research 70, 379–386.Google Scholar
Haigh, B, Hood, K, Broadhurst, M, Medele, S, Callaghan, M, Smolenski, G, Dines, M, Wheeler, T 2008. The bovine salivary proteins BSP30a and BSP30b are independently expressed BPI-like proteins with anti-Pseudomonas activity. Molecular Immunology 45, 1944–1951.CrossRefGoogle ScholarPubMed
Hakala, BE, White, C, Recklies, AD 1993. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. Journal of Biological Chemistry 268, 25803–25810.Google Scholar
Harris, P, Johannessen, KM, Smolenski, G, Callaghan, M, Broadhurst, MK, Kim, K, Wheeler, TT 2010. Characterisation of the anti-microbial activity of bovine milk ribonuclease4 and ribonuclease5 (angiogenin). International Dairy Journal 20, 400–407.Google Scholar
Hogarth, CJ, Fitzpatrick, JL, Nolan, AM, Young, FJ, Pitt, A, Eckersall, PD 2004. Differential protein composition of bovine whey: a comparison of whey from healthy animals and from those with clinical mastitis. Proteomics 4, 2094–2100.CrossRefGoogle ScholarPubMed
Hollis, BW, Roos, BA, Lambert, PW 1982. Vitamin D compounds in human and bovine milk. Advances in Nutrition Research 4, 59–75.Google Scholar
Hooper, LV, Stappenbeck, TS, Hong, CV, Gordon, JI 2003. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunology 4, 269–273.CrossRefGoogle ScholarPubMed
Isaacs, CE 2001. The antimicrobial function of milk lipids. Advances in Nutrition Research 10, 271–285.Google ScholarPubMed
Jacobsen, S, Niewold, TA, Kornalijnslijper, E, Toussaint, MJ, Gruys, E 2005. Kinetics of local and systemic isoforms of serum amyloid A in bovine mastitic milk. Veternary Immunology and Immunopathology 104, 21–31.Google Scholar
Jia, HP, Starner, T, Ackermann, M, Kirby, P, Tack, BF, McCray, PB Jr 2001. Abundant human beta-defensin-1 expression in milk and mammary gland epithelium. Journal of Pediatrics 138, 109–112.Google Scholar
Kailasapathy, K, Chin, J 2000. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunology and Cell Biology 78, 80–88.Google Scholar
Kawai, T, Akira, S 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology 11, 373–384.Google Scholar
Kehrli, ME Jr, Harp, JA 2001. Immunity in the mammary gland. The Veterinary Clinics of North America. Food Animal Practice 17, 495–516, vi.CrossRefGoogle ScholarPubMed
Koldovsky, O, Thornburg, W 1987. Hormones in milk. Journal of Pediatric Gastroenterology and Nutrition 6, 172–196.Google Scholar
Korhonen, H, Marnila, P, Gill, HS 2000. Milk immunoglobulins and complement factors. British Journal of Nutrition 84 (suppl. 1), S75–S80.Google Scholar
Lai, Y, Di Nardo, A, Nakatsuji, T, Leichtle, A, Yang, Y, Cogen, AL, Wu, ZR, Hooper, LV, Schmidt, RR, von Aulock, S, Radek, KA, Huang, CM, Ryan, AF, Gallo, RL 2009. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nature Medicine 15, 1377–1382.CrossRefGoogle ScholarPubMed
Larson, MA, Wei, SH, Weber, A, Mack, DR, McDonald, TL 2003. Human serum amyloid A3 peptide enhances intestinal MUC3 expression and inhibits EPEC adherence. Biochemical and Biophysics Research Communications 300, 531–540.Google Scholar
Le, A, Barton, LD, Sanders, JT, Zhang, Q 2011. Exploration of bovine milk proteome in colostral and mature whey using an ion-exchange approach. Journal of Proteome Research 10, 692–704.Google Scholar
Lee, CG 2009. Chitin, chitinases and chitinase-like proteins in allergic inflammation and tissue remodeling. Yonsei Medical Journal 50, 22–30.CrossRefGoogle ScholarPubMed
Lu, YC, Yeh, WC, Ohashi, PS 2008. LPS/TLR4 signal transduction pathway. Cytokine 42, 145–151.Google Scholar
Lutzow, YC, Donaldson, L, Gray, CP, Vuocolo, T, Pearson, RD, Reverter, A, Byrne, KA, Sheehy, PA, Windon, R, Tellam, RL 2008. Identification of immune genes and proteins involved in the response of bovine mammary tissue to Staphylococcus aureus infection. BMC Veterinary Research 4, 18.Google Scholar
Maes, P, Damart, D, Rommens, C, Montreuil, J, Spik, G, Tartar, A 1988. The complete amino acid sequence of bovine milk angiogenin. FEBS Letters 241, 41–45.Google Scholar
Miyazato, A, Nakamura, K, Yamamoto, N, Mora-Montes, HM, Tanaka, M, Abe, Y, Tanno, D, Inden, K, Gang, X, Ishii, K, Takeda, K, Akira, S, Saijo, S, Iwakura, Y, Adachi, Y, Ohno, N, Mitsutake, K, Gow, NA, Kaku, M, Kawakami, K 2009. Toll-like receptor 9-dependent activation of myeloid dendritic cells by Deoxynucleic acids from Candida albicans. Infection and Immunity 77, 3056–3064.Google Scholar
Molenaar, AJ, Harris, DP, Rajan, GH, Pearson, ML, Callaghan, MR, Sommer, L, Farr, VC, Oden, KE, Miles, MC, Petrova, RS, Good, LL, Singh, K, McLaren, RD, Prosser, CG, Kim, KS, Wieliczko, RJ, Dines, MH, Johannessen, KM, Grigor, MR, Davis, SR, Stelwagen, K 2009. The acute-phase protein serum amyloid A3 is expressed in the bovine mammary gland and plays a role in host defence. Biomarkers 14, 26–37.Google Scholar
Mosconi, E, Rekima, A, Seitz-Polski, B, Kanda, A, Fleury, S, Tissandie, E, Monteiro, R, Dombrowicz, DD, Julia, V, Glaichenhaus, N, Verhasselt, V 2010. Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunology 3, 461–474.CrossRefGoogle ScholarPubMed
Murakami, M, Dorschner, RA, Stern, LJ, Lin, KH, Gallo, RL 2005. Expression and secretion of cathelicidin antimicrobial peptides in murine mammary glands and human milk. Pediatrics Research 57, 10–15.CrossRefGoogle ScholarPubMed
Newburg, DS 2009. Neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans. Journal of Animal Science 87, 26–34.Google Scholar
Oftedal, OT 2002. The origin of lactation as a water source for parchment-shelled eggs. Journal of Mammary Gland Biology and Neoplasia 7, 253–266.Google Scholar
Oviedo-Boyso, J, Valdez-Alarcon, JJ, Cajero-Juarez, M, Ochoa-Zarzosa, A, Lopez-Meza, JE, Bravo-Patino, A, Baizabal-Aguirre, VM 2007. Innate immune response of bovine mammary gland to pathogenic bacteria responsible for mastitis. Journal of Infection 54, 399–409.CrossRefGoogle ScholarPubMed
Politis, I, Chronopoulou, R 2008. Milk peptides and immune response in the neonate. Advances in Experimental Medicine and Biology 606, 253–269.Google Scholar
Pryor, SM, Smolenski, GA, Wieliczko, RJ, Broadhurst, MK, Stelwagen, K, Wheeler, TT, Haigh, BJ 2010. Cathelicidin levels in milk from cows infected with a range of mastitis causing pathogens. Proceedings of the New Zealand Society of Animal Production 70, 243–245.Google Scholar
Rainard, P 2003. The complement in milk and defense of the bovine mammary gland against infections. Veterinary Research 34, 647–670.Google Scholar
Reid, G, Burton, J 2002. Use of Lactobacillus to prevent infection by pathogenic bacteria. Microbes and Infection 4, 319–324.CrossRefGoogle ScholarPubMed
Reiter, B 1978. Review of the progress of dairy science: antimicrobial systems in milk. Journal of Dairy Research 45, 131–147.CrossRefGoogle ScholarPubMed
Rejman, JJ, Hurley, WL 1988. Isolation and characterization of a novel 39 kilodalton whey protein from bovine mammary secretions collected during the nonlactating period. Biochemical and Biophysical Research Communications 150, 329–334.CrossRefGoogle ScholarPubMed
Scocchi, M, Wang, S, Zanetti, M 1997. Structural organization of the bovine cathelicidin gene family and identification of a novel member. FEBS Letters 417, 311–315.Google Scholar
Shah, C, Hari-Dass, R, Raynes, JG 2006. Serum amyloid A is an innate immune opsonin for Gram-negative bacteria. Blood 108, 1751–1757.CrossRefGoogle ScholarPubMed
Smolenski, G, Haines, S, Kwan, FY, Bond, J, Farr, V, Davis, SR, Stelwagen, K, Wheeler, TT 2007. Characterisation of host defence proteins in milk using a proteomic approach. Journal of Proteome Research 6, 207–215.Google Scholar
Smolenski, GA, Wieliczko, RJ, Pernthaner, A, Broadhurst, MK, Stelwagen, K, Hein, WR, Wheeler, TT, Haigh, BJ 2010. Cathelicidin: a potential diagnostic marker for early detection of mastitis in dairy cows. In Mastitis research into practise: 5th IDF Mastitis Conference (ed. JE Hillerton), pp. 545–551. VetLearn, Christchurch, New Zealand.Google Scholar
Sordillo, LM, Shafer-Weaver, K, DeRosa, D 1997. Immunobiology of the mammary gland. Journal of Dairy Science 80, 1851–1865.Google Scholar
Swanson, K, Gorodetsky, S, Good, L, Davis, S, Musgrave, D, Stelwagen, K, Farr, V, Molenaar, A 2004. Expression of a beta-defensin mRNA, lingual antimicrobial peptide, in bovine mammary epithelial tissue is induced by mastitis. Infection and Immunity 72, 7311–7314.Google Scholar
Verhasselt, V 2010. Oral tolerance in neonates: from basics to potential prevention of allergic disease. Mucosal Immunology 3, 326–333.CrossRefGoogle ScholarPubMed
von Mutius, E, Vercelli, D 2010. Farm living: effects on childhood asthma and allergy. Nature Reviews Immunology 10, 861–868.Google Scholar
Vorbach, C, Capecchi, MR, Penninger, JM 2006. Evolution of the mammary gland from the innate immune system? Bioessays 28, 606–616.Google Scholar
Wang, L, Lashuel, HA, Walz, T, Colon, W 2002. Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel. Proceedings of the National Academy of Sciences USA 99, 15947–15952.CrossRefGoogle ScholarPubMed
Wheeler, TT, Hodgkinson, AJ, Prosser, CG, Davis, SR 2007. Immune components of colostrum and milk – a historical perspective. Journal of Mammary Gland Biology and Neoplasia 12, 237–247.Google Scholar
Yang, D, Chen, Q, Su, SB, Zhang, P, Kurosaka, K, Caspi, RR, Michalek, SM, Rosenberg, HF, Zhang, N, Oppenheim, JJ 2008a. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. Journal of Experimental Medicine 205, 79–90.Google Scholar
Yang, W, Zerbe, H, Petzl, W, Brunner, RM, Gunther, J, Draing, C, von Aulock, S, Schuberth, HJ, Seyfert, HM 2008b. Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder. Molecular Immunology 45, 1385–1397.Google Scholar