Escape from bacterial iron piracy through rapid evolution of transferrin

Mutations in human TF that hinder bacterial iron piracy are associated with host resistance to N. meningitidis infection.

“Of note, mutations in human TF which hinder bacterial iron piracy are associated with host resistance to N. mengitidis infection (Barber and Elde, 2014).”

Sequence and structural data from hominid transferrins indicate an evolutionary arms race between bacterial receptors and the human C-lobe of transferrin.

“Analysis of hominid transferrin sequences and structures has yielded evidence of a mutational ‘arms race’ between bacterial receptors evolving to bind and take up transferrin as a source of iron, whereas the human C-lobe of transferrin, which is targeted by these receptors84, has evolved mutational variants that escape uptake by these bacteria.”

Diferric transferrin prevents non-transferrin bound iron from engaging in Fenton chemistry and deprives invading pathogens of free iron.

“This diferric Tf conjugate (Tf-Fe3+) not only prevents free, non-transferrin bound iron (NTBI), from engaging in Fenton chemistry to produce dangerous hydroxyl radicals, but also deprives invading pathogens of free iron to block their expansion and proliferation (Barber and Elde, 2014).”

Polymorphisms in host genes encoding iron-binding proteins that counter microbial siderophores or other iron uptake systems enhance resistance to bacterial infections.

“Along this line, polymorphisms in host genes encoding Fe-binding proteins that counter microbial siderophores or other microbial Fe uptake systems enhance resistance to bacterial infections [34].”

Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes.

“Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes”

Transferrin has undergone strong positive selection in primates.

“Not only has transferrin been subject to strong positive selection in primates”

The authors' recent work identified iron competition as a new interface for Red Queen conflicts.

“Our recent work highlighted the battle for iron as a new interface for Red Queen evolutionary conflicts [36].”

Rapidly evolving sites in primate transferrin almost completely overlap the TbpA binding interface.

“rapidly evolving sites almost entirely overlap with the binding interface of a bacterial surface receptor, transferrin-binding protein A (TbpA)”

Single amino acid changes at rapidly evolving transferrin sites can control TbpA binding specificity among related primates and for the human C2 variant.

“Single amino acid substitutions at rapidly evolving sites in transferrin were sufficient to control TbpA-binding specificities between related primates as well as for an abundant human transferrin variant, termed C2 (Figure 2B).”

Single rapidly evolving transferrin sites can dictate TbpA-binding differences between humans and chimpanzees.

“Our recent work further demonstrated that single rapidly evolving sites in transferrin are sufficient to dictate TbpA-binding differences between even our closest relatives, such as chimpanzees [36].”

Nutritional immunity has strongly affected host fitness during human evolutionary history with microbes.

“More broadly, these results demonstrate that nutritional immunity, similar to more established immune pathways, has strongly impacted host fitness during our long and intertwined history with microbes.”

Positive selection signatures at the transferrin-TbpA interface suggest this interaction was a key infection determinant over millions of years of primate divergence.

“Genetic signatures of positive selection at the transferrin–TbpA binding interface suggest that this interaction has been a key determinant of infection during millions of years of primate divergence.”

Primate Tf shows evidence of positive evolutionary selection at amino acid residues bound by bacterial Tf receptors.

“Primate Tf shows evidence of positive evolutionary selection at amino acid residues bound by bacterial Tf receptors, indicating the evolutionary pressure on the host to deprive pathogens of iron and the importance of Tf for host defence. 123”

Positive selection on primate Tf indicates evolutionary pressure on the host to deprive pathogens of iron and the importance of Tf for host defence.

“Primate Tf shows evidence of positive evolutionary selection at amino acid residues bound by bacterial Tf receptors, indicating the evolutionary pressure on the host to deprive pathogens of iron and the importance of Tf for host defence. 123”

Co-evolution of humans and pathogens has produced an evolutionary arms race in nutritional immunity.

“suggesting that the co-evolution of humans and pathogens has produced an evolutionary arms race in the context of nutritional immunity [217,218].”

Human and primate transferrin has undergone positive selection at the interface of binding by bacterial transferrin receptors.

“the human and primate iron-binding protein transferrin has undergone positive selection at the interface of binding by bacterial transferrin receptors”

Transferrin genetic variation among apes is the result of rapid evolution to counteract bacterial iron piracy.

“Elegant evolutionary work showed that transferrin genetic variation among apes is the result of rapid evolution to counteract bacterial iron piracy (10).”

Several pathogens are able to acquire transferrin-bound iron.

“In addition, several pathogens are able to acquire TF-bound iron [51–54].”