Fig 4. Model of lactoferrin evolution and genetic conflicts with pathogens.

Following a duplication of the transferrin gene in the ancestor of eutherian mammals, interactions between the transferrin (yellow) C lobe and the bacterial transferrin receptors such as TbpA (green) led to the emergence of a molecular arms race. In contrast, while lactoferrin has likely also been engaged in evolutionary conflicts with pathogen iron acquisition receptors like LbpA (purple), the emergence of antimicrobial peptide activity in the N lobe would have provided novel defense activity against pathogens targeting lactoferrin as an iron source. This function would have led to the emergence of pathogen inhibitors of lactoferrin antimicrobial peptide activity (such as PspA or LbpB), which have dominated subsequent evolutionary conflicts localized to the lactoferrin N lobe.