Photosensing proteins drive the spread of a bacterial infection that costs cattle farms in Brazil and Argentina up to $100 million a year.

Photosensing proteins are used by all forms of life, from bacteria and plants to butterflies and humans. These proteins absorb blue light, change shape and trigger other events within a cell. They are involved in plant phototropism, the movement of aquatic bacteria, and the regulation of mammalian circadian rhythms. New evidence shows they can also drive the spread of infectious disease.

A group of researchers including Howard Hughes Medical Institute international research scholar Fernando A. Goldbaum has discovered that photosensing proteins drive the spread of cattle brucellosis, a bacterial infection that costs cattle farms in Brazil and Argentina up to $100 million a year.

At some point in its life cycle, the bacterium comes out of an organism, senses blue light, and prepares itself to infect another organism.

Fernando A. Goldbaum

The findings were published in the August 24, 2007, issue of the journal Science. Goldbaum is chief of the Laboratory of Structural and Molecular Immunology at the Leloir Institute in Buenos Aires, Argentina. The senior author of the paper is Roberto A Bogomolni from the University of California, Santa Cruz. Trevor E. Swartz, also at UC-Santa Cruz, is the paper's first author. Other coauthors are from the Carnegie Institute of Washington, the National University of San Martin in Argentina, the University of Wisconsin, Madison, and Stanford University.

In cattle, brucellosis, also called Malta fever or Bang's disease, is caused by Brucella abortus. Affected cows abort calves late in pregnancy or give birth to weak offspring. The disease is spread when other cows lick the calves or eat grass contaminated by amniotic fluid. Bulls can be infected, but rarely spread the disease.

Humans can also contract brucellosis, usually by drinking unpasteurized milk. The disease, which causes flu-like symptoms, is treated with antibiotics, but is difficult to cure. In South America, human brucellosis is a significant problem because the infection in animals has not been brought under control.

Goldbaum and his colleagues found that light exposure primes B. abortus to replicate, increasing its chances of infecting a new host. “At some point in its life cycle, the bacterium comes out of an organism, senses blue light, and prepares itself to infect another organism,” Goldbaum said.

The Brucella photosensor is made of two components: a protein called LOV (for light-oxygen-voltage) and a protein called HK (for histidine kinase). The LOV-HK protein works like other photosensing proteins. It absorbs photons of blue light and uses this energy to create a bond between itself and a nearby flavin molecule (FMN). This activates the enzyme, which then catalyzes a reaction that can alter gene expression.

To test whether B. abortus' photosensing protein was necessary for infection, the group created a strain of the bacteria that lacked LOV-HK. They cultivated this knockout strain, as well as normal bacteria, with immune cells called macrophages. The normal B. abortus replicated and infected macrophages at much higher rates than the knockout strain, confirming that the bacteria need LOV-HK for optimal replication and infection.

The group also found that growing B. abortus in the dark reduced its ability to infect macrophages.

The discovery that the spread of brucellosis is driven by light makes sense from an evolutionary standpoint, Goldbaum said, since Brucella is a close relative of the soil bacteria Rhizobium and Agrobacterium. Normally, B. abortus lives in the dark inside an animal. But when an infected placenta is expelled or an infected cow is milked--exposing the bacteria to light and activating the photosensing system--the bacteria must find a new host.

Goldbaum and his colleagues also studied two other species of bacteria: Erythrobacter litoralis, a marine bacterium, and Pseudomonas syringae, which causes disease in a wide range of plants. In both, LOV-HK was active when the bacteria were exposed to blue light. But in contrast to Brucella, in which the photosensor remained active more than two hours after the environment was darkened, the flavin-protein bond in the other two organisms broke within about 30 minutes. The relative stability of the system in Brucella may have evolved to give the bacteria time to successfully infect another animal, Goldbaum said.

Identical LOV-HK proteins are found in Brucella species that infect hogs, sheep, and goats. More than 20 other species of bacteria have very similar LOV-HK proteins. “The fact that we found this in Brucella opens the possibility of studying the system elsewhere,” Goldbaum said.

Still, the discovery was a complete surprise, Goldbaum said. The group actually was looking for an oxygen sensor. Because Brucella often survives in low-oxygen, low-nutrient environments, Goldbaum surmised that it must have a way to sense whether its immediate surroundings were suitable.

The new information has set Goldbaum on a somewhat modified road to his goal of finding out all he can about Brucella. “In the future, this research may lead to a point of attack for drug design,” he said. “But we still need to know more. We are still focused on the role of flavin metabolism on virulence. And we are still looking for an oxygen sensor.”

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