Durham, N.C. – A newly discovered mechanism by which an infectious fungus perceives light also plays an important role in its virulence, according to Howard Hughes Medical Institute investigators at Duke University Medical Center. The findings suggest that changes in light following fungal invasion of the human body may be an important and previously overlooked cue that sparks infection, the researchers said.
The discovery in the human pathogen Cryptococcus neoformans further suggests that light therapy, in combination with anti-fungal drug treatments, might offer an effective method to combat a variety of fungal infections, particularly those of the skin or nails, said HHMI investigator Joseph Heitman, M.D., James B. Duke professor of molecular genetics and microbiology and medicine at Duke.
Light therapy is now used for medical conditions, such as seasonal affective disorder. The most common method, called bright-light therapy, requires that patients sit near a special light box fitted with high-intensity, full-spectrum or white light bulbs. UV irradiation is also used to repigment skin affected by the autoimmune disorder vitiligo.
The findings also have important implications for understanding early fungal evolution, Heitman and study lead author Alexander Idnurm, Ph.D., reported in a forthcoming issue of Public Library of Science Biology, published online March 15, 2005. The National Institute for Allergy and Infectious Diseases and the Burroughs Wellcome Fund supported the research.
The potentially life-threatening fungus C. neoformans invades the central nervous system to cause disease, most commonly in patients who lack a functioning immune system, such as organ transplant recipients, those with HIV/AIDS, and patients treated with steroids or cancer chemotherapy. The fungus' global importance as a health threat has therefore risen in parallel with the increase in immunosuppressive therapies and the worldwide HIV/AIDS epidemic.
Light normally inhibits mating of C. neoformans. The Duke team has now identified two genes responsible for that light response. Loss of the same genes also reduces fungal virulence in mice, they reported.
Earlier studies had linked the genes to light-sensing in another distantly related fungal lineage, an indication that the fungal light sensor arose early in evolution and may be shared by many extant fungal species. Other well-studied fungi, such as Saccharomyces cerevisiae, or baker's yeast, have apparently lost their ability to sense light, Heitman said, and have neither of the conserved light-sensing proteins.
"Fungi have many negative implications for human life as they lead to human disease, as well as plant disease and mold," said Idnurm, a post-doctoral fellow at Duke. "However, fungi also play important beneficial roles, for example, as a source of food and pharmaceuticals.
"Therefore, an understanding of the role of environmental signals such as light in fungal development is vital to increase the benefits and decrease the costs that fungi present."
The researchers first tested the importance of genes with known roles in light sensitivity of another, distantly related fungus. Yeast strains lacking one of those genes, known as white collar 1 (BWC1), mated equally well in the light or the dark, implicating that gene in the fungus' ability to sense light. BWC1 also functions in the fungus' resistance to ultraviolet light, they reported. Further study identified a second, related gene, BWC2, that is also required for C. neoformans normal response to both blue and ultraviolet light.
Moreover, the researchers found, mice inoculated with C. neoformans lacking either of the light-sensing genes remained healthy 30 days later, while those infected with the normal fungus died by day 30.
The finding points to novel virulence pathways, Heitman said, as the BWC1 and BWC2 mutants were not impaired for any of the characteristics previously linked to virulence.
"The genes required for light sensing, while not essential for virulence, do contribute to the rapidity with which the fungus causes lethal infection in the mammalian host," Heitman said. "It is therefore conceivable that light could be used as a therapy for fungal infections, particularly infections at the body surface, such as those of skin or nails." Laser therapy might also be possible for certain fungal sinus infections, he added.
The finding that Cryptococcus shares its light-sensing mechanism with other distantly related fungi also has important implications for understanding fungal evolution, Heitman said. The researchers speculate that evolution of these light-sensing genes more than 400 million years ago may have had major significance for fungal colonization of land, at a time when UV irradiation was particularly intense.
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