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Light Therapy May Combat Fungal Infections, New Evidence Suggests

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Duke Health News 919-660-1306

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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