You’re probably not aware of it, but when you’re suffering from a bad case of food poisoning or another infection, bacteria are busy stealing iron from you. Many microbes use special chemicals to snatch away the metal, which they need to reproduce. But this need could be their downfall, according to new research. For the first time, two separate groups have developed candidate vaccines that protect against infection by targeting iron-scavenging molecules. The shots didn't prevent disease in mice, but they did slow down infection, showing the concept might work.
Iron is a hot commodity inside the human body. The metal is essential for producing energy and replicating DNA; it has a starring role in hemoglobin, the protein that carries oxygen inside red blood cells. Bacteria also need iron to grow and divide, and they have special molecules called siderophores that bind to the metal and rip it right out of the proteins in which it is ensconced. Siderophores then ferry the precious cargo back to the bacterial cell by binding to a specialized receptor.
Scientists have tried to exploit this mechanism by devising vaccines that unleash antibodies against the receptors. A few have shown promise, but the receptors repel water and are insoluble, making the vaccine harder to manufacture. An alternative approach is to target the siderophores themselves. The problem is that siderophores aren’t naturally good at revving up the immune system, since they’re so small. To make them more visible to B cells and other immune responders, two groups of scientists decided to hook up synthesized siderophores to so-called carrier proteins, large proteins that the immune system views as “foreign,” and try the resulting conjugates as vaccines.
A group at the University of Michigan in Ann Arbor designed a vaccine targeting the siderophores of Escherichia coli urinary tract infections, while a team at Massachusetts Institute of Technology and the University of California (UC), Irvine, took aim at a Salmonella strain that causes food poisoning. Each group immunized mice with their conjugate; several weeks later, they challenged the animals with a big dose of bacteria.
As the researchers reported in a pair of papers in the Proceedings of the National Academy of Sciences this month, the siderophore shots didn't prevent disease; vaccinated mice still developed infections, many of which were severe. But vaccinated mice had dramatically fewer bacteria in their bodies compared with mice that received a dose of the carrier protein alone. In the E. coli study, for instance, vaccinated mice had at least 10 times fewer E. coli in their urine and kidneys, which—along with their bladders—were less inflamed than those of control mice. In the Salmonella experiments, bacterial numbers were as much as 20,000-fold lower in the vaccinated mice and scientists also identified antibodies specific to the siderophores that seem responsible for the protection.
These results are important, say the researchers, but they are still first steps. “It was kind of long shot, but it worked,” says Manuela Raffatellu, a microbiologist at UC Irvine and a senior author on the Salmonella study. “It's certainly not ready for prime time,” concedes Harry Mobley, a bacteriologist who led the E. coli study at Michigan. Nevertheless, he’s “very excited about the finding." Mobley hopes that a similar vaccine can be tested in humans 5 years from now. Because related species of disease-causing bacteria often produce chemically similar siderophores, a single vaccine might work against a variety of different bacteria, he says.
Eric Skaar, a microbiologist at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved with the work, calls the findings “pretty impressive.” “Any time two different groups have very similar results using similar strategies, it really speaks to the robustness," he says. The results provide an important proof of concept, adds James Johnson, an infectious disease physician at the Minneapolis Veterans Administration Health Care System in Minnesota. He says such vaccines could be an alternative to antibiotics, which are becoming increasingly ineffective and often wipe out good bacteria as well: “We really do need to push this line of investigation further because of the antibiotic resistance crisis we're having now.”