Escape from bacterial iron piracy through rapid evolution of transferrin

Abstract

Iron sequestration provides an innate defense termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.

Role of Autophagy in the Maintenance of Intestinal Homeostasis

“…63, 64 The role of autophagy in iron homeostasis also has implications for pathogen defense, as bacteria scavenge iron from infected host cells and a “molecular arms race” has been posited in the evolution of host and bacterial iron-binding proteins. 65 Autophagy has also been demonstrated to mediate recycling of lipids in the form of lipid droplets, as will be discussed below.…”

Evolution of host specialization in gut microbes: the bee gut as a model

“…Opportunistic pathogens such as Neisseria and Haemophilus have evolved receptors to pick up iron in host-bound molecules of transferrin, leading to a co-evolutionary arms race and accelerated adaptive evolution at the responsible loci in both host and microbe. 39 Like V. fischeri, host specificity for the nematode symbiont Xenorhabdus can be mediated by a single locus. Here, the genes nilABC are unique to strains infecting the nematode Steinernema carpocapsae but are absent in other Xenorhabdus; heterologous expression of nilABC in the other Xenorhabdus enable their colonization of S. carpocapsae.…”

A comparative, cross-species investigation of the properties and roles of transferrin- and lactoferrin-binding protein B from pathogenic bacteria

“…It is generally accepted that the progenitor for Lf arose through a Tf gene duplication event that occurred at time period related to the development of the mammalian lineage (Lambert et al 2005), as this ultimately enabled Lf to develop additional roles without compromising the critical role of Tf in iron homeostasis. Positive selection analysis has attributed sequence variation in Tf (Barber and Elde 2014) and Lf (Liang and Jiang 2010) to sites of interaction with bacterial proteins that bind the host glycoproteins or the peptides released by proteolysis of Lf (lactoferricin and lactoferrampin). Since it is becoming more evident that both Tf and Lf may be available on mucosal surfaces as sources of iron for growth (Anderson et al 2003), and since the upper respiratory and genitourinary tract is the only ecological niche for the Gram-negative bacteria that have developed receptors for these host glycoproteins, the selective forces in this environment are most likely driving the evolving interface between the bacterial and host proteins.…”

“…Positive selection analysis of primate Tfs primarily identified sites on the C-lobe of Tf involved in binding to the TonB-dependent integral outer membrane protein TbpA (Barber and Elde 2014) and included sites that were responsible for the exquisite host specificity of receptors from human pathogens for specific primate transferrins (Gray-Owen and Schryvers 1993). In contrast, positive selection analysis of Lfs from a broad range of mammalian species primarily identified sites within the N-lobe of Lf, in spite of the fact that, analogous to TbpA, the meningococcal LbpA primarily interacts with the C-lobe of Lf (Wong and Schryvers 2003).…”