The effects of lactoferrin on gram-negative bacteria

Lactoferrin is an iron-binding protein found in human mucosal secretions as well as the specific granules of polymorphonuclear leukocytes. A variety of functions have been ascribed to the protein, and it appears to contribute to antimicrobial host defense. In particular, it has been shown to have direct effects on pathogenic microorganisms including bacteriostasis and the induction of microbial iron uptake systems. Still its overall physiologic role remains to be defined. It has appeared logical that antimicrobial activity of the protein arises from sequestration of environmental iron thereby causing nutritional deprivation in susceptible organisms. This argument is buttressed by the finding that selected highly virulent pathogens have evolved techniques to subvert this effect and use the protein as an iron source. However, recent observations indicate that the protein has additional properties that contribute to host defense. Work by several groups has shown that the protein synergistically interacts with immunoglobins, complement, and neutrophil cationic proteins against Gram-negative bacteria. Further, both the whole protein and a cationic N-terminus peptide fragment directly damage the outer membrane of Gram-negative bacteria suggesting a mechanism for the supplemental effects. This review will summarize these diverse observations with a consideration of how the in vitro work relates to the physiological role of the protein.