Lactoferrin receptors in Gram-negative bacteria: an evolutionary perspective

Abstract

In this short review, we outline the major events that led to the development of iron acquisition systems in Gram-negative bacteria and mammals since the beginning of life on earth. Naturally, the interaction between these organisms led to the development of a wonderfully complex set of protein systems used for competition over a once prevalent (but no longer) biocatalytic cofactor. These events led to the appearance of the lactoferrin gene, which has since been exploited into adopting countless new functions, including the provision of highly bactericidal degradation products. In parallel to lactoferrin’s evolution, evolving bacterial receptors have countered the bactericidal properties of this innate immunity protein.

Lactoferrin: A glycoprotein that plays an active role in human health

“…Furthermore, Lf has been shown to be involved in a variety of physiological and protective effects. Some of the most studied to date include antimicrobial activity, antiviral, cell proliferation and differentiation, cytokine regulation, inflammatory response, and immunomodulatory activity (17)(18)(19). However, the cellular and molecular mechanisms by which Lf regulates inflammatory, antiviral, and immune responses have not been fully elucidated.…”

Targeting bacterial transferrin and lactoferrin receptors for vaccines

“…The evolutionary process for development of Tf receptors likely initially involved a single-component receptor (Figure 2, middle panel) arising from an ancestral TBDT that transported ferric iron and ultimately being replaced by a more efficient two-component receptor (Figure 2, right panel) that arose by around 320 million years ago [4]. Since Tf has iron preferentially bound to its C-lobe under most physiological conditions, and is the lobe bound by the bipartite receptor ( (i.e., a single-lobed TbpB precursor), it argues strongly for the importance of the bi-lobed TbpB in enhancing the efficiency of iron acquisition from Tf under physiological conditions in the upper respiratory tract but experimental evidence is lacking.…”

“…An appreciation of the critical role that the Tf and Lf receptors play in the survival of bacteria and their proliferation on the mucosal surface is best acquired by reflecting on how Tf and Lf receptors ultimately arose and evolved as part of an ongoing adaptation to iron availability during development of life on earth [ 4 ]. Possession of these receptor proteins enable the bacteria to proliferate independently from other members of the microbial community and cause localized or systemic infections, making the receptor proteins ideal targets for vaccines.…”

“…Analysis of the sequence changes on the surface of primate Tfs indicate that residues involved in binding to the bacterial receptor protein TbpA were preferentially mutating and ultimately responsible for the host specificity within primates over a 40-million-year time span [ 16 ]. Extension of this observation to explain the specificities of receptors in mammalian [ 17 ] and avian species [ 18 ] indicates that Tf has been available on mucosal surfaces for at least 320 million years, when the ancestral lineages leading to birds and mammals diverged [ 4 ]. An early indication of the differences between mammalian and avian receptor proteins, that could readily be isolated with Tf affinity isolation methods, was first noticed when primers designed to the conserved NEVTGLGCK and GAINEIEYE motifs [ 15 ] were able to amplify a product from genomic DNA isolated from bacteria that inhabit mammalian hosts but not from bacteria that inhabit avian hosts.…”

TbpBY167A-Based Vaccine Can Protect Pigs against Glässer’s Disease Triggered by Glaesserella parasuis SV7 Expressing TbpB Cluster I

“…G. parasuis , Actinobacillus pleuropneumoniae and A. suis are capable of acquiring iron from porcine transferrin for growth in low-iron environments such as the mucosal surface by expressing a transferrin (Tf) receptor that steals iron from porcine transferrin [ 8 , 9 ]. The strict host specificity of the Tf receptors limits the niche of the bacterial pathogens to a specific host that involved the coevolution of Tf and Tf receptors in a process that occurred over millions of years [ 10 ], suggesting that the surface Tf receptors likely arose in Gram-negative bacterial ancestors over 320 million years ago [ 11 ]. Thus, the receptors in the three porcine pathogens come from a common ancestor, which is why the overall diversity of the receptor proteins is distributed amongst the three species [ 9 ].…”