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Loss of Enzyme Cripples Common Fungal Infection

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Duke Health News 919-660-1306

DURHAM, N.C. -- Disrupting a single enzyme in a fungus
responsible for a significant percentage of hospital-acquired
infections prevents the organism from becoming potentially
fatal, found a new study by Howard Hughes Medical Institute
researchers at Duke University Medical Center.

The finding identifies a new target for drugs to fight the
illness, called candidiasis, said Joseph Heitman, M.D., an HHMI
investigator and director of Duke's Center for Microbial
Pathogenesis. The research was reported in the June 2003 issue
of the journal Eukaryotic
Cell
.

The researchers studied the molecular machinery of the
fungus Candida albicans, which accounts for more than 10
percent of hospital-acquired infections. The condition is fatal
in up to 40 percent of patients who contract the invasive form
of the illness.

C. albicans occurs naturally in the body, where it lives on
the surface of the intestines, esophagus and other internal
body surfaces. Benign bacteria normally help keep the fungus in
check, Heitman said. Natural immune defenses in the blood of
healthy people also prevent the fungus from infecting the
bloodstream.

"But sometimes that natural balance gets tipped and the
fungus begins growing out of control," Heitman added. The most
familiar results are yeast infections, including vaginitis and
thrush, an infection of the oropharynx.

In immunocompromised people -- such as patients who have
undergone organ transplantation, have late-onset diabetes, or
are taking broad-spectrum antibiotics -- the result can be more
serious. The fungus can invade the bloodstream and progress to
full-blown candidiasis.

The researchers suspected that C. albicans' switch from a
benign to a pathogenic form must require the fungus to sense
and respond to changes in its environment. That theory led them
to an enzyme called calcineurin, a protein important for
mediating stress responses in fungi and plants.

To test the idea that calcineurin is critical for the
virulence of C. albicans, the researchers infected laboratory
mice with either normal C. albicans or a mutant strain that
lacked calcineurin.

Mice infected with the intact fungus died by the eighth day
after infection, the researchers found. In contrast, 27 of 30
mice infected with the mutant strain survived until 30 days
later, the team reported.

To understand the underlying cause of the mutant strains'
lost virulence, the researchers tested its ability to undergo
transitional steps known to be important in candidal
pathogenesis -- survival at high temperatures, filamentous
growth and host cell adherence and invasion -- in laboratory
cultures.

However, the mutant and normal fungus showed no differences
in any of the tested characteristics of infection.

"That calcineurin is essential to fungal virulence was
absolutely clear," said Heitman. "But when we asked why, we
found that none of the characteristics known to be important in
infection could explain it."

Since the main cause of death in mice with candidiasis is
acute infection of the kidneys, the researchers studied the
kidneys of mice infected with the mutant fungus, finding that
they contained many fewer fungal cells than those infected with
the normal fungus. Further studies revealed that the mutant
fungal cells survived and grew at much lower levels in serum,
the soluble component of blood, than normal fungal cells.

"When we grew the cells in test tubes with serum, the mutant
fungal cells began gradually disappearing after six hours,"
said first author of the study Jill Blankenship, also of Duke.
"By nine hours the difference between the mutant and wild-type
fungus was even more pronounced." After 24 hours, the mutant
fungal cells had nearly all died, while the normal cells had
increased by more than 14,000-fold.

"The result was a big surprise," Heitman said. "Nobody had
recently studied survival in blood as an important step in
fungal pathogenesis. The finding suggests an alternate means of
preventing the transformation of C. albicans from a benign
fungus to a serious disease and could lead to new
treatments."

Calcineurin plays a role in the virulence of a second fungal
pathogen Cryptococcus neoformans, according to the team's
earlier work, which suggests that drugs targeting the enzyme
may provide broad-spectrum antifungal action, Heitman
added.

Today only a handful of treatments exist for treating such
fungal infections, Heitman said. Of those, one of the most
commonly prescribed medications, fluconazole (trade name
Diflucan), often fails to completely eliminate the infection. A
second alternative developed in 1957, amphotericin B,
frequently has serious side effects including fever, chills,
muscle aches and kidney toxicity.

A next step in the research, said Heitman, will be to
identify the blood component responsible for the mutant fungus'
failure to invade the bloodstream.

Other Duke researchers involved in the study include Floyd
Wormley, Ph.D., Molly Boyce, Wiley Schell and John Perfect,
M.D. Scott Filler, M.D., of the Harbor-UCLA Research and
Education Institute in Torrance, Calif., also contributed to
the study.

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