Escape from bacterial iron piracy through rapid evolution of transferrin

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Science  12 Dec 2014:
Vol. 346, Issue 6215, pp. 1362-1366
DOI: 10.1126/science.1259329

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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.

The frontline of host-pathogen coevolution

Pathogens have to subvert a host's innate defenses to avoid being killed. Barber and Elde now show that this principle extends to nutrient-transporting proteins, such as transferrin, which binds iron (see the Perspective by Armitage and Drakesmith). Without iron, invading pathogens cannot replicate, but iron is sequestered in transferrin, which stops pathogens using it. So pathogens have evolved a succession of transporters that can hijack transferrin's iron. Over time, the primate transferrin binding surface has coevolved to wrestle iron back from the grip of pathogens.

Science, this issue p. 1362; see also p. 1299

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