|
By Phil Williams
pwilliam@franklin.uga.edu
New research from microbiologists at UGA, published in the journal Science, demonstrates that Borrelia burgdorferi, the bacterium that causes Lyme disease in humans, is the first pathogenic  bacterium identified that does not need or use iron.
“All bacterial pathogens described to date have developed specialized systems to acquire iron from their hosts,” says Frank Gherardini. “Current dogma states that to be successful in humans, bacteria must overcome strict iron limitations that the human body imparts on them. Although iron is abundant in humans, the amount of free iron is well below the levels required to support the growth of most bacteria. To our surprise, we found that B. burgdorferi doesn’t even require iron. In fact, iron is extremely toxic to it.”
Understanding how these bacteria are able to colonize humans and cause disease will ultimately lead researchers to more effective ways to prevent and control the disorder.
Some 30 years ago, doctors were puzzled by a large number of arthritis cases in children who lived near Lyme, Conn. After exhaustive study, they discovered that the disorder, which has symptoms that vary in kind and severity, was caused by a bacterium transferred to humans from the bite of the deer tick, Ixoides scapularis. Since then, there have been major efforts to understand the bacterium and its life cycle, and Gherardini’s lab has been involved for a number of years, publishing many papers on the subject. Gherardini’s graduate student James E. Posey was co-author on the recent paper published in Science.
Borrelia burgdorferi is a spiral-shaped organism, a spirochete. Some scientists believe that Lyme disease came from Europe a century ago but was only recently detectable when it became more common. A resurgent population of deer, along with mice--the reservoir host for the bacterium--coupled with increased outdoor activities by humans, has helped ensure spread of the disease.
The Lyme disease microbe is extremely difficult to isolate or culture, so most doctors look for evidence of the rash at the site of the tick bite or for antibodies to B. burgdorferi in the blood. Despite available tests and therapies, many cases go undiagnosed for months. Humans with late-stage Lyme disease are largely out of luck, and doctors can only treat the symptoms. Although people don’t die from Lyme disease, the attendant joint discomfort and other symptoms can create ongoing misery. That’s why laboratories are still working hard to understand the ways in which Borrelia infects and survives in its hosts.
Until recently, Gherardini says, standard wisdom held that all bacterial pathogens require iron. The new finding probably doesn’t indicate that Borrelia evolved a life cycle designed not to need iron.
On the other hand, natural-selection pressure on the entire genome clearly made it possible for Borrelia to exist without iron, though why remains unclear.
The studies in Gherardini’s lab were helped immeasurably by the fact that the genome for Borrelia burgdorferi has been completely analyzed, so scientists know the location of the bug’s genes on its chromosomes--and what these genes do.
The proof the researchers needed came slowly and painstakingly. First, they showed that the activities of several common iron-dependent enzymes were undetectable in cell extracts. Second, they found no iron-containing proteins in the bacterium during an analysis of the complete genome sequence. Third, B. burgdorferi grew normally in the presence of high levels of iron-limiting compounds, and fourth, the bacterium doesn’t appear to alter gene expression in response to iron-limiting conditions.
Finally, using mass spectroscopy and radioactive-iron transport techniques, they found that the levels of iron inside the cells of B. burgdorferi are 1,000-fold less than those measured in other pathogenic bacteria.
“Uptake experiments using iron suggest that B. burgdorferi does not transport iron, and there are less than five atoms of iron per cell,” says Gherardini. To date, Lactobacillus planatarum, a free-living soil bacterium, is the only other organism for which experimental data demonstrate that iron is not required for growth. Apparently, B. burgdorferi belongs to a unique category of pathogenic bacteria that use a novel strategy to overcome iron limitation in the human host.
Just how this new discovery can be used--to develop either new vaccines or new therapies for those infected with Lyme disease--is not yet clear. A vestigial iron pathway may still exist in Borrelia burgdorferi, so simply adding iron to a diet or as a medical therapy would do little good. Still, because other metals such as manganese are used by the bacterium, the discovery of how iron is unneeded by the bug could point toward an entirely new way to limit the occurrence and severity of the disease in humans.
“The ultimate goal of the bacterium is not to wipe out the host,” says Gherardini. “It’s just to find another place to live. This should tell us a lot about how they do that.”
|
|
|
