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Discovery of genetic pathways may help combat fungus

A new study has uncovered the genetic wiring diagram underlying the infectiousness of Candida albicans, a fungus that causes thrush in babies, vaginal infections in women, and life-threatening infections in chemotherapy and AIDS patients.

The study, led by Dr. Gerald R. Fink, MIT professor of biology and director of the Whitehead Institute for Biomedical Research, reveals that one key to Candida's infectiousness lies in its ability to switch from a rounded form to filamentous forms. When the wiring diagram underlying this switch is inactivated, Candida infections are no longer deadly in mice.

The implications of these results for humans are enormous, given that current treatment options for invasive fungal infections are seriously limited. "If we could design drugs that inactivate or block Candida's filamentation pathways, we might be able to fight the organism's insidious and devastating effects on patients with weak immune systems," said Professor Fink. "Our study also shows that this genetic pathway is a common theme among fungal pathogens and so may provide important insights on how plant and animal pathogens work."

The results were reported in the September 5 issue of Cell by first author Hsiu-Jung Lo and her colleagues from Professor Fink's lab, Children's Hospital in Boston, and Schering-Plough Research Institute in Kenil-worth, NJ.

Using state-of-the-art videomi-croscopy techniques, Professor Fink and his associates recently captured on video the fate of immune cells infected with Candida in a petri dish. When Candida enters a host, the organism is eaten up by cells called macrophages, which are the sentinels of the immune system. But soon, the fungi fight back, switching to a filamentous form and tearing through the macrophage walls, destroying them. In people with healthy bone marrow, other immune system cells called neutrophils come to the rescue to destroy the filamentous Candida. However, in patients with weakened immune systems who lack healthy bone marrow and do not make neutrophils, this second line of attack is not available.

The scientists reported that two parallel genetic pathways account for Candida's ability to filament, and that inactivating one pathway is not enough to stop filamentation. Inactivating both pathways, on the other hand, renders Candida harmless to both macrophages and mice.

Fungal infections in hospitalized patients have almost doubled throughout the 1980s, often with life-threatening results in individuals with weakened immune systems. Candida in particular is associated with high mortality rates in chemotherapy patients, and it is also a major cause of infection to other patients, including burn victims and premature babies.

Finding these new ways for physicians to combat these infections has been a challenge. For one, developing broad-spectrum antibiotics against fungi has been difficult. Fungi are more similar to humans than to bacteria, and few antifungal agents can kill fungi without harming normal human cells. The drug fluconazole is one of the few antibiotics that works without severe side effects, but increasingly, physicians are encountering fungal strains that are resistant to fluconazole.

Scientists had suspected that a key to Candida's infectiousness lay in its ability to switch to one of several filamentous forms, but until recently, they had hardly attempted to figure out this wiring diagram because Candida albicans, the most common pathogen, is asexual and therefore intractable for genetic studies. Although common baker's yeast is an excellent system for genetic studies, scientists had never considered it to be a good model for studying fungal disease because they thought yeast couldn't switch to a filamentous form.

However, four years ago, Professor Fink and his colleagues discovered that yeast cells could filament, opening new doors for research into fungal infections. In this study, they used molecular biology techniques to identify the components of the filamentation circuit in yeast. With the recently completed yeast genome to guide them, the scientists began to knock out suspicious genes and, by a process of elimination, discovered the culprits responsible for filamentation. Once scientists identified the key yeast filamentation genes, they simply plucked out the analogous genes in Candida.

"Candida albicans is 300 million years apart evolutionarily from yeast -- as far away in evolution as humans are from turtles -- and yet the basic logic circuit was conserved," said Professor Fink.

But more work needed to be done before scientists could think about reaping the benefits of this remarkable discovery. The key question was whether preventing filamentation in Candida could render the fungus noninfectious.

Scientists began to answer this question using macrophages in a petri dish, which are normally ineffective against filamentous Candida. When challenged by Candida strains with both pathways knocked out, macrophages emerged victorious. This was good news to researchers, but the real test would come when the Fink lab scientists, in collaboration with scientists at Schering Plough, began experiments with mice.

Infections by Candida -- even with strains having only one filamentation pathway knocked out -- are generally lethal in mice. But when the scientists infected mice with Candida strains with both pathways knocked out, the mice did not succumb.

Based on Professor Fink's work, other scientists at Purdue University have knocked out analogous genes in a strain of fungus that causes disease in rice plants, rendering the fungus harmless. These findings will have implications for agriculture.

The work reported in Cell was supported by grants from the NIH and Schering-Plough Research Institute, and a National Research Service Award. Professor Fink is an American Cancer Society Professor of Genetics.

A version of this article appeared in MIT Tech Talk on September 17, 1997.

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