, Volume 23, Issue 3, pp 377–386 | Cite as

The lactoferrin receptor complex in gram negative bacteria

  • Amanda J. Beddek
  • Anthony B. Schryvers


Bacteria that inhabit the respiratory and genitourinary tracts of mammals encounter an iron-deficient environment on the mucosal surface where iron is complexed by the host iron-binding proteins transferrin and lactoferrin. Lactoferrin is also present in high concentrations at sites of inflammation where the cationic anti-microbial peptide lactoferricin is produced by proteolysis of lactoferrin. Several members of the Neisseriaceae and Moraxellaceae families express surface receptors, capable of specifically binding host lactoferrin and extracting the iron from lactoferrin as a source of iron for growth. The receptor is comprised of an integral outer membrane protein, lactoferrin binding protein A (LbpA), and a largely exposed surface lipoprotein, lactoferrin binding protein B (LbpB). LbpA is essential for mediating growth using lactoferrin as a sole iron source whereas LbpB only plays a facilitating role. LbpB, with the presence of a large tract of negatively charged residues, appears to protect the bacterial cell from the bactericidal effects of the lactoferricin. The lactoferrin receptors in these species appear to be essential for survival and thus may serve as potential vaccine targets.


Lactoferrin Iron utilisation Lactoferrin binding Lactoferricin Gram negative bacteria Neisseria Moraxella 



We would like to thank Rolando Pajon for generating the structural model for LbpB and Jessmi Ling for assistance in preparing the manuscript.


  1. Alcantara J, Padda JS, Schryvers AB (1992) The N-linked oligosaccharides of human lactoferrin are not required for binding to bacterial lactoferrin receptors. Can J Microbiol 38:1202–1205PubMedCrossRefGoogle Scholar
  2. Alcantara J, Yu R-H, Schryvers AB (1993) The region of human transferrin involved in binding to bacterial transferrin receptors is localized in the C-lobe. Mol Microbiol 8(6):1135–1143CrossRefPubMedGoogle Scholar
  3. Alugupalli KR, Kalfas S, Edwardsson S, Naidu AS (1995) Lactoferrin interaction with actinobacillus actinomycetemcomitans. Oral Microbiol Immunol 10:35–41CrossRefPubMedGoogle Scholar
  4. Anderson JE, Hobbs MM, Biswas GD, Sparling PF (2003) Opposing selective forces for expression of the gonococcal lactoferrin receptor. Mol Microbiol 48(5):1325–1337CrossRefPubMedGoogle Scholar
  5. Arnold RR, Russel JE, Champion WJ, Brewer M, Gauthier JJ (1982) Bactericidal activity of human lactoferrin: differentiation from the stasis of iron deprivation. Infect Immun 35:792–797PubMedGoogle Scholar
  6. Baker EN, Baker HM, Kidd RD (2002) Lactoferrin and transferrin: functional variations on a common structural framework. Biochem Cell Biol 80(1):27–34CrossRefPubMedGoogle Scholar
  7. Baltes N, Hennig-Pauka I, Gerlach GF (2002) Both transferrin binding proteins are virulence factors in actinobacillus pleuropneumoniae serotype 7 infection. FEMS Microbiol Lett 209(2):283–287CrossRefPubMedGoogle Scholar
  8. Bellamy W, Takase M, Wakabayashi H, Kawase K, Tomita M (1992) Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J Appl Bacteriol 73:472–479PubMedGoogle Scholar
  9. Biswas GD, Anderson JE, Chen CJ, Cornelissen CN, Sparling PF (1999) Identification and functional characterization of the Neisseria gonorrhoeae lbpB gene product. Infect Immun 67(1):455–459PubMedGoogle Scholar
  10. Bonnah RA, Schryvers AB (1998) Preparation and characterization of Neisseria meningitidis mutants deficient in the production of the human lactoferrin binding proteins LbpA and LbpB. J Bacteriol 180(12):3080–3090PubMedGoogle Scholar
  11. Bonnah RA, Yu R-H, Schryvers AB (1995) Biochemical analysis of lactoferrin receptors in the neisseriae: identification of a second bacterial lactoferrin receptor protein. Microb Pathog 19(5):285–297CrossRefPubMedGoogle Scholar
  12. Bonnah RA, Yu R-H, Wong H, Schryvers AB (1998) Biochemical and immunological properties of lactoferrin binding proteins from Moraxella (Branhamella) catarrhalis. Microb Pathog 24(2):89–100CrossRefPubMedGoogle Scholar
  13. Bonnah RA, Wong H, Loosmore SM, Schryvers AB (1999) Characterization of Moraxella (Branhamella) catarrhalis lbpB, lbpA and lactoferrin receptor orf3 isogenic mutants. Infect Immun 67(3):1517–1520PubMedGoogle Scholar
  14. Brenner DJ, Krieg NR, Staley JT, Garrity GM (2004) Bergey’s manual of systematic bacteriology: the proteobacteria, vol 2. Springer, New YorkGoogle Scholar
  15. Buchanan SK, Smith BS, Venkatramani L, Xia D, Esser M, Palnitkar M, Chakraborty R, van der Helm D, Deisenhofer J (1999) Crystal structure of the outer membrane active transporter FepA from Escherichia coli. Nat Struct Biol 6(1):56–63CrossRefPubMedGoogle Scholar
  16. Cornelissen CN, Kelley M, Hobbs MM, Anderson JE, Cannon JG, Cohen MS, Sparling PF (1998) The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers. Mol Microbiol 27(3):611–616CrossRefPubMedGoogle Scholar
  17. Desai P, Garges E, Genco C (2000) Pathogenic neisseriae can use hemoglobin, transferrin, and lactoferrin independently of the tonB locus. J Bacteriol 182:5586–5591CrossRefPubMedGoogle Scholar
  18. Dhaenens L, Szczebara F, Husson MO (1997) Identification, characterization, and immunogenicity of the lactoferrin-binding protein from Helicobacter pylori. Infect Immun 65(2):514–518PubMedGoogle Scholar
  19. Du R, Wang Q, Yang Y-P, Schryvers AB, Chong P, England D, Klein MH, Loosmore SM (1998) Cloning and expression of the Moraxella catarrhalis lactoferrin receptor genes. Infect Immun 66(8):3656–3664PubMedGoogle Scholar
  20. Ferguson AD, Hofmann E, Coulton JW, Diederichs K, Welte W (1998) Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide. Science 282(5397):2215–2220CrossRefPubMedGoogle Scholar
  21. Gifford JL, Hunter HN, Vogel HJ (2005) Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties. Cell Mol Life Sci 62(22):2588–2598CrossRefPubMedGoogle Scholar
  22. Gray-Owen SD, Schryvers AB (1996) Bacterial transferrin and lactoferrin receptors. Trends Microbiol 4(5):185–191CrossRefPubMedGoogle Scholar
  23. Harbitz O, Jenssen AO, Smidsrod O (1984) Lysozyme and lactoferrin in sputum from patients with chronic obstructive lung disease. Eur J Respir Dis 65(7):512–520PubMedGoogle Scholar
  24. Khun HH, Kirby SD, Lee BC (1998) A Neisseria meningitidis fbpABC mutant is incapable of using nonheme iron for growth. Infect Immun 66(5):2330–2336PubMedGoogle Scholar
  25. Kijlstra A, Jeurissen SH, Koning KM (1983) Lactoferrin levels in normal human tears. Br J Ophthalmol 67(3):199–202CrossRefPubMedGoogle Scholar
  26. Kolsto Otnaess AB, Meberg A, Sande HA (1983) Plasma lactoferrin measured by an enzyme-linked immunosorbent assay (ELISA). Measurements on adult and infant plasma. Scand J Haematol 31(3):235–240PubMedCrossRefGoogle Scholar
  27. Lee BC, Bryan LE (1989) Identification and comparative analysis of the lactoferrin and transferrin receptors among clinical isolates of gonococci. J Med Microbiol 28:199–204CrossRefPubMedGoogle Scholar
  28. Lee BC, Schryvers AB (1988) Specificity of the lactoferrin and transferrin receptors in Neisseria gonorrhoeae. Mol Microbiol 2:827–829CrossRefPubMedGoogle Scholar
  29. Lissolo L, Maitre-Wilmotte G, Dumas P, Mignon M, Danve B, Quentin-Millet M-J (1995) Evaluation of transferrin-binding protein 2 within the transferrin- binding protein complex as a potential antigen for future meningococcal vaccines. Infect Immun 63(3):884–890PubMedGoogle Scholar
  30. Lonnerdal B, Iyer S (1995) Lactoferrin: molecular structure and biological function. Annu Rev Nutr 15:93–110CrossRefPubMedGoogle Scholar
  31. Mickelsen PA, Sparling PF (1981) Ability of Neisseria gonorrhoeae, Neisseria meningitidis, and commensal Neisseria species to obtain iron from transferrin and iron compounds. Infect Immun 33:555–564PubMedGoogle Scholar
  32. Mickelsen PA, Blackman E, Sparling PF (1982) Ability of Neisseria gonorrhoeae, Neisseria meningitidis, and commensal Neisseria species to obtain iron from lactoferrin. Infect Immun 35:915–920PubMedGoogle Scholar
  33. Moraes TF, Yu R-H, Strynadka NC, Schryvers AB (2009) Insights into bacterial iron acquisition: the structure of transferrin binding protein B from actinobacillus pleuropneumoniae. Molecular Cell 35:523–533CrossRefPubMedGoogle Scholar
  34. Moshynskyy I, Jiang M, Fontaine MC, Perez-Casal J, Babiuk LA, Potter AA (2003) Characterization of a bovine lactoferrin binding protein of Streptococcus uberis. Microb Pathog 35(5):203–215CrossRefPubMedGoogle Scholar
  35. Naidu AS, Miedzobrodzki J, Andersson M, Nilsson L-E, Forsgren A, Watts JL (1990) Bovine lactoferrin binding to six species of coagulase-negative staphylococci isolated from bovine intramammary infections. J Clin Microbiol 28:2312–2319PubMedGoogle Scholar
  36. Naidu AS, Miedzobrodzki J, Musser JM, Rosdahl VT, Hedström S-Å, Forsgren A (1991) Human lactoferrin binding in clinical isolates of Staphylococcus aureus. J Med Microbiol 34:323–328CrossRefPubMedGoogle Scholar
  37. Naidu AS, Andersson M, Forsgren A (1992) Identification of a human lactoferrin-binding protein in Staphylococcus aureus. J Med Microbiol 36:177–183CrossRefPubMedGoogle Scholar
  38. Oakhill JS, Sutton BJ, Gorringe AR, Evans RW (2005) Homology modelling of transferrin-binding protein A from neisseria meningitidis. Protein Eng Des Sel 18:221–228CrossRefPubMedGoogle Scholar
  39. Ogunnariwo JA, Schryvers AB (1996) Rapid identification and cloning of bacterial transferrin and lactoferrin receptor protein genes. J Bacteriol 178:7326–7328PubMedGoogle Scholar
  40. Ogunnariwo JA, Schryvers AB (2001) Characterization of a novel transferrin receptor in bovine strains of Pasteurella multocida. J Bacteriol 183(3):890–896CrossRefPubMedGoogle Scholar
  41. Pettersson A, Van der Ley P, Poolman JT, Tommassen J (1993) Molecular characterization of the 98-kilodalton iron-regulated outer membrane protein of Neisseria meningitidis. Infect Immun 61:4724–4733PubMedGoogle Scholar
  42. Pettersson A, Van der Biezen J, Joosten V, Hendriksen J, Tommassen J (1999) Sequence variability of the meningococcal lactoferrin-binding protein LbpB. Gene 231(1–2):105–110CrossRefPubMedGoogle Scholar
  43. Pettersson A, Kortekaas J, Weynants VE, Voet P, Poolman JT, Bos MP, Tommassen J (2006) Vaccine potential of the neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB. Vaccine 24(17):3545–3557CrossRefPubMedGoogle Scholar
  44. Price GA, Masri HP, Hollander AM, Russell MW, Cornelissen CN (2007) Gonococcal transferrin binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice. Vaccine 25(41):7247–7260CrossRefPubMedGoogle Scholar
  45. Redhead K, Hill T, Chart H (1987) Interaction of lactoferrin and transferrins with the outer membrane of bordetella pertussis. J Gen Microbiol 133:891–898PubMedGoogle Scholar
  46. Retzer MD, Yu R-H, Zhang Y, Gonzalez GC, Schryvers AB (1998) Discrimination between apo and iron-loaded forms of transferrin by transferrin binding protein B and its N-terminal subfragment. Microb Pathog 25(4):175–180CrossRefPubMedGoogle Scholar
  47. Retzer MD, Yu R-H, Schryvers AB (1999) Identification of sequences in human transferrin that bind to the bacterial receptor protein, transferrin-binding protein B. Mol Microbiol 32(1):111–121CrossRefPubMedGoogle Scholar
  48. Rokbi B, Mignon M, Maitre-Wilmotte G, Lissolo L, Danve B, Caugant DA, Quentin-Millet M-J (1997) Evaluation of recombinant transferrin binding protein B variants from Neisseria meningitidis for their ability of induce cross reactive and bactericidal antibodies against a genetically diverse collection of serogroup B strains. Infect Immun 65(1):55–63PubMedGoogle Scholar
  49. Schryvers AB, Lee BC (1989) Comparative analysis of the transferrin and lactoferrin binding proteins in the family Neisseriae. Can J Microbiol 35(3):409–415CrossRefPubMedGoogle Scholar
  50. Schryvers AB, Morris LJ (1988a) Identification and characterization of the human lactoferrin-binding protein from Neisseria meningitidis. Infect Immun 56:1144–1149PubMedGoogle Scholar
  51. Schryvers AB, Morris LJ (1988b) Identification and characterization of the transferrin receptor from Neisseria meningitidis. Mol Microbiol 2:281–288CrossRefPubMedGoogle Scholar
  52. Schryvers AB, Stojiljkovic I (1999) Iron acquisition systems in the pathogenic neisseria. Mol Microbiol 32:1117–1123CrossRefPubMedGoogle Scholar
  53. Senkovich O, Cook WJ, Mirza S, Hollingshead SK, Protasevich DEB II, Chattopadhyay D (2007) Structure of a complex of human lactoferrin N-lobe with pneumococcal surface protein a provides insight into microbial defence mechanism. J Mol Biol 370(4):701–713CrossRefPubMedGoogle Scholar
  54. Shaper M, Hollingshead SK, Benjamin WH Jr, Briles DE (2004) PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin [corrected]. Infect Immun 72(9):5031–5040CrossRefPubMedGoogle Scholar
  55. Staggs TM, Greer MK, Baseman JB, Holt SC, Tryon VV (1994) Identification of lactoferrin-binding proteins from Treponema pallidium subspecies pallidum and Treponema denticola. Mol Microbiol 12(4):613–619CrossRefPubMedGoogle Scholar
  56. Stojiljkovic I, Srinivasan N (1997) Neisseria meningitidis tonB, exbB, and exbD genes: ton- dependent utilization of protein-bound iron in Neisseriae. J Bacteriol 179(3):805–812PubMedGoogle Scholar
  57. Teng CT (2002) Lactoferrin gene expression and regulation: an overview. Biochem Cell Biol 80(1):7–16CrossRefPubMedGoogle Scholar
  58. Tigyi Z, Kishore AR, Mæland JA, Forsgren A, Naidu AS (1992) Lactoferrin-binding proteins in Shigella flexneri. Infect Immun 60:2619–2626PubMedGoogle Scholar
  59. Tryon VV, Baseman JB (1987) The acquisition of human lactoferrin by Mycoplasma pneumoniae. Microb Pathog 3:437–443CrossRefPubMedGoogle Scholar
  60. Ward PP, Paz E, Conneely OM (2005) Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 62(22):2540–2548CrossRefPubMedGoogle Scholar
  61. Weinberg ED, Weinberg GA (1995) The role of iron in infection. Curr Opin Infect Dis 8:164–169CrossRefGoogle Scholar
  62. West D, Reddin K, Matheson M, Heath R, Funnell S, Hudson M, Robinson A, Gorringe A (2001) Recombinant Neisseria meningitidis transferrin binding protein A protects against experimental meningococcal infection. Infect Immun 69(3):1561–1567CrossRefPubMedGoogle Scholar
  63. Wong H, Schryvers AB (2003) Bacterial lactoferrin binding protein a binds to both domains of the human lactoferrin C-lobe. Microbiology 149:1729–1737CrossRefPubMedGoogle Scholar
  64. Yu R-H, Schryvers AB (1993a) The interaction between human transferrin and transferrin binding protein 2 from Moraxella (Branhamella) catarrhalis differs from that of other human pathogens. Microb Pathog 15:443–445CrossRefGoogle Scholar
  65. Yu R-H, Schryvers AB (1993b) Regions located in both the N-lobe and C-lobe of human lactoferrin participate in the binding interaction with bacterial lactoferrin receptors. Microb Pathog 14:343–353CrossRefPubMedGoogle Scholar
  66. Yu R-H, Schryvers AB (2002) Bacterial lactoferrin receptors: insights from characterizing the Moraxella bovis receptors. Biochem Cell Biol 80:81–90CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Department of Microbiology and Infectious DiseasesUniversity of CalgaryCalgaryCanada

Personalised recommendations