An Evolutionary Battle Against Bacteria

Every disease has a history. Some of that history is written in books, and some is written in our DNA.

The earliest records of meningitis — an infection of the membranes that line the brain — reach back to 1685. The British physician Thomas Willis described fevered patients, some of whom suffered from “continual raving” and others who suffered from “horrible stiff extensions in the whole body.”

But meningitis was a threat long before Willis put quill to paper.

In a new  study, published Thursday in the journal Science, two University of Utah scientists have uncovered a 40-million-year struggle between our ancestors and the bacteria that cause meningitis: As our ancestors evolved new defenses, our enemies evolve counter-defenses. By understanding the history of this struggle, we may be able to fight meningitis more effectively in the future.

A number of species of bacteria can cause meningitis, but two — Haemophilus influenzae and Neisseria meningitidis — are the top threats. Like all bacteria, these pathogens need iron to grow. But we don’t make it easy for them to find iron inside our bodies.

To move iron atoms from one cell to another, we seal them inside a kind of molecular lockbox, called transferrin. A cell can load two iron atoms into a single transferrin molecule and deliver it to another cell, which draws the transferrin inside and then opens it.

Transferrin lets us starve bacteria by making free iron atoms scarce. Simply withholding it from the bacteria “becomes an immune strategy,” said Nels C. Elde, an evolutionary geneticist and an author of the new study.

A few years ago, Dr. Elde became puzzled by transferrin. Studies by other scientists suggested that it had experienced strong natural selection, changing its molecular structure over generations. But transferrin still does the same job it has been doing for hundreds of millions of years. It ferries iron atoms inside mammals, reptiles, amphibians and even fish.

To understand what has driven transferrin’s evolution, Dr. Elde teamed with Matthew F. Barber, a postdoctoral researcher in his lab. They carried out an unprecedented study on the evolution of the gene that encodes transferrin, comparing our own version to those in 20 species of apes and monkeys.

The two scientists confirmed that over the past 40 million years, our transferrin protein had undergone drastic changes. Transferrin is made up of two lobes, each of which grabs an iron atom. By far the most changes had occurred in only one of the lobes. The other one barely evolved.

This finding gave Dr. Elde a clue as to what was driving the evolution of transferrin: meningitis-causing bacteria.

Neisseria and Haemophilus can both steal iron from transferrin. They do so with a protein, TbpA, that pries open one of transferrin’s two lobes, exposing the iron atom inside. The lobe under attack is the one that has been evolving swiftly; the unmolested lobe has barely changed.

As the two Utah scientists were studying these evolutionary changes, researchers at the National Institutes of Health published the molecular details of how TbpA grabs transferrin. When Dr. Barber and Dr. Elde compared their results with the molecular structure, they were shocked. Almost every point at which transferrin made contact with TbpA has evolved, while little has changed beyond them.

“That was the moment it all snapped together,” said Dr. Elde.

Dr. Barber and Dr. Elde were able to reconstruct the history of transferrin. Each time its shape changed, it became harder for the bacteria to grab it and steal its iron.

The scientists wondered if the bacteria had evolved in response to these changes. To find out, they got strains of Haemophilus influenzae and Neisseria meningitis from patients. They looked at the bacteria’s TbpA genes to see where they had evolved new structures.

It turns out they changed where they made contact with transferrin. “It’s basically a mirror image,” said Dr. Elde.

He and Dr. Barber argue that our ancestors and meningitis-causing bacteria have been locked in an arms race for 40 million years. Each time we make it harder for the bacteria to steal our iron, the bacteria change their structure to get a better grip on our transferrin.

The race isn’t over. A new variant of transferrin has evolved in humans, and it is found in 6 to 25 percent of people, depending on their ethnic group. The Utah scientists found that Haemophilus influenzae bacteria can’t steal iron from the new variant. “It’s basically invisible,” Dr. Elde said.

Harmit S. Malik, an evolutionary geneticist at the Fred Hutchinson Cancer Research Center who was not involved in the research, said that until he saw it, he doubted there were enough clues left in living primates to reconstruct the evolutionary arms race.

But Dr. Barber and Dr. Elde proved him wrong. “It’s an extremely crisp result,” Dr. Malik said, adding, “Frankly, I didn’t think this could be done.”

Despite all the defenses our ancestors evolved against these bacteria, they still pose a major threat to humanity. Haemophilus influenzae alone has been  estimated to kill 371,000 people a year. Some researchers have investigated  treating such infections by giving patients extra transferrin to starve bacteria.

Dr. Malik suggested that this treatment would be even more effective if scientists used the evolutionary history of transferrin as a guide for designing transferrin that the bacteria can’t attack.

“I suspect it could be a very, very important therapeutic,” he said. If he is right, our monkeylike ancestors could have a hand in saving the lives of our descendants.