Our genomes reveal the evolutionary battle between human hosts and bacterial “iron pirates” over the protein transferrin that transports iron in the bloodstream, according to two University of Utah genetics researchers, Matthew Barber and Nels Elde, whose talk at the 2013 ASCB Annual Meeting previewed their full paper, which was just published in Science.
Even pathogens need a balanced diet, according to Elde and Barber. Bacteria require trace metals, including iron, to conduct the basic chemistry of life. While most free-living bacteria go about their hunt for nutrients in relative obscurity, when pathogenic bacteria take up residence in a human host, the hunt for iron becomes a complex game of “hide and seek.” Indeed, one of the most potent defenses against infection, the researchers say, is to withhold trace metals from pathogenic bacteria, a process termed “nutritional immunity.”
This battle for iron has been going on for a long, long time, say Barber and Elde, evolutionary biologists in the Department of Human Genetics at Utah. Their work has focused on tracing the evolutionary history of transferrin, which serves as the primary iron transport protein in the bloodstream. Iron in the blood is tightly bound by circulating transferrin, which is then delivered to host cells via surface receptors that cause cellular uptake of transferrin-iron complexes. This provides the host with a two-for-one advantage by transporting essential iron to host cells and simultaneously contributing to nutritional immunity.
However, several pathogens have adapted countermeasures against this host defense. Bacteria such as Haemophilus influenzae encode TbpA, a transferrin surface receptor, which recognizes circulating host transferrin and removes the iron bound to it. This strategy of iron piracy has been known for several years, but the impact of this process on host evolution has not been previously investigated.
Reasoning that the battle between the mammalian transferrin and bacterial encoded transferrin receptors such as TbpA would be evident in the history of mutations found in the genes for these proteins, Barber and Elde analyzed the DNA sequences of transferrin across diverse primates, including humans. Evolution at host-pathogen interfaces would be driven by strong natural selection, which they believed would be evident in the ongoing emergence and retention of adaptive gene mutations.
The researchers compared transferrin sequences from 20 primate genomes and observed unusually rapid accumulation of mutations with a strong bias for substitutions that alter protein composition. Strikingly, mutations are concentrated at the interface between transferrin and bacterial transferrin receptors. These observations are consistent with a “molecular arms race” during which transferrin mutations that prevent recognition by bacterial transferrin receptors are repeatedly maintained by natural selection. This in turn places pressure on the pathogen to regain its crucial iron source.
In their Science paper, the researchers show in particular how human C2 transferrin polymorphism evades TbpA variants in H. influenzae, providing what they say is functional basis for understanding genetic variation. “Our work demonstrates that nutritional immunity has played a fundamental role in the survival of primate populations challenged by bacterial pathogens,” write Barber and Elde. “By illuminating the battle for iron as a major driving force of host-pathogen evolution, from 40 million years of primate divergence to emerging human epidemics today, our studies reveal new reservoirs of genetic resistance to infectious diseases.”
About the Author:
John Fleischman was the ASCB Senior Science Writer from 2000 to 2016. Best unpaid perk of the job? Working with new grad students and Nobel Prize winners.
