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MIT researchers find similar genetic culprit behind chronic infection of plants and mammals

Knowledge could result in brucellosis vaccine for humans

CAMBRIDGE, Mass. -- Researchers at the Massachusetts Institute of Technology and Louisiana State University Health Sciences Center at Shreveport report in the March 31 issue of Science that they have found surprising similarities in how two bacteria with widely different lifestyles manage to establish chronic infections in mammals and plants.

Among other things, this information potentially could lead to a vaccine for human brucellosis, a debilitating disease also known as undulant fever.

At first glance, the agriculturally important bacterium Rhizobium meliloti and the pathogen Brucella abortus, which causes brucellosis in cows and humans, don't have much in common. But there are intriguing similarities in the ways the two bacteria interact with their hosts, even though rhizobia form a mutually beneficial association with plants and brucellae produce disease in mammals, said Graham C. Walker, professor of biology at MIT.

All living organisms require nitrogen. Plants cannot use the nitrogen gas in the atmosphere unless it is converted to ammonia, a form of nitrogen found in fertilizer. Leguminous plants such as alfalfa accomplish this conversion naturally with the help of rhizobia, microorganisms that live in the soil.

The bacteria rhizobia set up house by invading nodules on the roots of legumes like alfalfa. At the end of an elaborate invasion process, the plant's cells engulf the rhizobia much the way white blood cells engulf intruders. "You can look at it as a chronic infection of the plant, although unlike other infections, this is beneficial to the organism," Walker said. "The plant allows itself to be invaded by the bacteria. In this way, the plant gets ammonia and the bacteria gets carbon."


It turns out that the bacterial gene bacA is crucial for these two very different host-bacterial relationships. Walker's group had previously identified this key gene in the rhizobia that interact with alfalfa. MIT postdoctoral fellow Kristin LeVier set out to finda potentially similar gene in a bacterial pathogen that infects mammals. She focused on a mammalian pathogen, Brucella abortus,so-called because it is the bacterium responsible for brucellosis, a disease that causes infected cows to abort their fetuses. She found that brucellae possessed a gene extremely similar to rhizobia's bacA.

"Because of the close evolutionary connections between the rhizobia and brucellae bacteria and the parallels between how each interacts with its host, we though it might be possible to use knowledge obtained from studies of plant-rhizobial symbioses to gain insights into the poorly understood mechanisms that enable the brucellae to establish chronic infections in their mammalian hosts," Walker said.

Stringent regulations requiring entire cattle herds to be destroyed if even one cow is infected have effectively eliminated brucellosis in the U.S., but the disease is epidemic in some developing countries. Caused by coming into contact with infected animals or by ingesting infected milk, milk products or animal tissue, brucellosis is a hard-to-treat infection whose symptoms include fever, malaise and weight loss. It is difficult to wipe out with antibiotics because brucellae live inside human cells.

"The brucellae appear to have an insidious ability to foil the mammal's immune system and rebuild its population from the few cells that survive the first onslaught of the body's immune system," said Martin Roop, associate professor of microbiology and immunology at Louisiana State University Health Sciences Center (LSUHSC) at Shreveport.

If the bacA gene is removed from Rhizobium meliloti, the mutant bacteria are able to carry out the early steps of invading the plant nodule but cannot establish a chronic infection and therefore cannot fix nitrogen. When LeVier created a mutant strain of Brucella abortus that was missing the bacA gene, she found something surprising when she used the bacteria to infect mice: the mutant bacteria entered the animals' white blood cells and survived for two weeks. But then, instead of continuing to flourish, the numbers of bacterial cells dropped significantly and the infection cleared from the mice.

"The bacA function seems to be necessary for the bacteria to overcome the defense response of the host that would otherwise prevent a chronic infection," Walker said.

This scenario, in which removal of bacA from the brucellae allows the body's immune system to recognize and then successfully kill off a persistent intruder, is a perfect basis for the development of a vaccine, LeVier points out. There is currently no vaccine against human brucellosis. The bacA protein also may be an interesting target for the development of new antibiotics

In addition, insights into the mechanism underlying the ability of the brucellae to chronically infect host cells may also apply to other types of bacteria. This information also could help develop nitrogen-fixation systems for plants that do not normally fix nitrogen, which has long been a worldwide goal of agricultural, ecological and economic importance.

This work is funded by grants from the National Institute of General Medical Science and U.S. Department of Energy&emdash;Life Sciences Research Foundation and a contract from the U.S. Army Medical Research and Materiel Command to LSUHSC--Shreveport.

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