May 14, 2003 CAMBRIDGE, Mass. (May 13, 2003) –– When a few weeds appear on your front lawn, you can easily pick them off one by one. But if they start taking over the yard, the picking becomes laborious, and you may need to turn to a chemical weed-killer to hold the invaders in check. After several applications of the herbicide, however, the weeds could become resistant, forcing you to use an even more powerful solution. Meanwhile, the survival of your lawn hangs in the balance.
Like weeds in a lawn, pathogenic fungi and yeasts (single-celled fungi) can invade and overtake our bodies. In people with healthy immune systems, cells called macrophages and neutrophils engulf these pathogens, nipping them in the bud. But when the immune system is weakened by disease or drugs, fungi – much like weeds in your garden – can grow unchecked.
For example, when the neutrophil cell count is low, an invasion of the common yeast Candida albicans can cause a systemic infection. The result can be an overgrowth of the yeast in various organs – and possibly death. In such cases, physicians often turn to anti-fungal drugs to keep the yeast under control. But over time, yeasts and fungi can develop resistance to the treatments, forcing medical researchers to devise more potent drugs. Meanwhile, the patient's health hangs in the balance.
From Harmless to Harmful
For millennia, yeasts and fungi have enjoyed relatively good relations with humans. Despite their abundance – they appear on plant leaves and flowers, soil, salt water, baked goods and beer, as well as in our gastrointestinal tracts and skin surfaces – very few yeasts and fungi trigger disease in healthy people. Present in about half of us, the most common fungal pathogen, Candida albicans, can cause easily treatable ailments such as vaginitis, diaper rash and oral thrush. But according to recent reports, yeasts and fungi are impacting some people much more severely: An increasing number of hospital patients with compromised immune systems are succumbing to fungal pathogens, leading to thousands of deaths each year.
"Fungal pathogens are becoming much more prevalent in systemic infections because we have a larger immunocompromised patient population," says Robert T. Wheeler, a postdoctoral fellow in the lab of Gerald Fink, a Member and former director at Whitehead Institute for Biomedical Research. This includes cancer, AIDS and organ transplant patients. If these patients are infected by the Candida species – the fourth most common bloodstream infection in hospitals – they face a nearly 40 percent mortality rate. Treatment is limited to a small number of marginally effective anti-fungal drugs that produce significant side effects and to which the pathogens are becoming increasingly resistant. "Antibiotics can kill bacteria without bad side effects, but because fungi contain cellular machinery and proteins similar to our own, it's hard to find agents to kill fungi that don't have negative effects on us," Wheeler explains.
Probing the Immune System Response
Containing the "weeds" within us requires novel approaches. Researchers in Fink's lab are investigating more virulent forms of fungi to improve our understanding of how fungal pathogens interact with the immune system, and to develop more effective anti-fungal agents.
"People used to study pathogens by taking a microorganism and debilitating it by making a mutation," observes Fink, who also is a professor of genetics at Massachusetts Institute of Technology. "But these debilitated organisms weren't very informative about the healthy pathogen. A much more fruitful approach is if you make something that's hypervirulent, because genes that lead to a souped-up microbe tell you a great deal about how pathogens behave."
A case in point is an experiment that Wheeler, Fink and collaborators at Boston University and Israel's Tel Aviv University published earlier this year on Saccharomyces cerevisiae (baker's yeast). Used in bread baking, beer brewing and wine fermentation, Saccharomyces has appeared more often in immunocompromised patients, raising several questions about its origin, survival and virulence in humans.
In their study, which appeared in the Feb. 14 Proceedings of the National Academy of Sciences, the scientists compared the virulence in laboratory mice of Saccharomyces strains isolated from the human bloodstream, a rotting fig and a carefully cultivated, fully sequenced strain of baker's yeast strains. These comparisons were made before and after knocking out a gene called SSD1, which contributes to the yeast cells' surface characteristics and to their ability to grow at higher temperatures.
In mice, without gene modification, the lab strain and human isolate were not virulent while the fig isolate was virulent. But when the scientists knocked out the SSD1 gene, they found that the virulence of the plant and clinical strains rose substantially. Wheeler and his colleagues determined that the removal of SSD1 changed the composition and cell wall architecture of the yeast cell surface. The mutant yeast also evoked a more powerful response from immune cells. As a result, the researchers suggest, the immune system's macrophage cells may have misrecognized the yeasts and overreacted, provoking an imbalance in the immune system – a systematic inflammatory response that ultimately caused the mice to die of septic shock.
What's significant about this study is that it probes the minimum requirement for fungi to cause disease, says Phillips Robbins, professor of molecular and cell biology at Boston University's School of Dental Medicine. "Defining the subtle mutations that lead to this pathogenic lifestyle will provide important new insights into the primary or underlying mechanisms used by other more aggressive fungi to produce disease," Robbins maintains.
Wheeler expects this study to accelerate efforts to understand how the immune system detects pathogenic yeast. "We aim to understand which molecular patterns of the yeast are recognized by the immune system, and how it responds," he says. "The more you understand how the innate immune system works, the more you can enable people to respond better to pathogens, and learn how to regulate the immune system when it gets out of control."
Research Thrusts at the Fink Lab and Beyond
Researchers at Whitehead take a broad-based approach to the study of pathogenic yeasts and fungi, combining new genomic approaches and genetic techniques to boost scientists' knowledge of how fungal pathogens infect human, animal and plant hosts. "We're trying to understand the basic mechanisms of growth, development, pathogenesis and virulence of these organisms," says Wheeler, "in a way that we hope sheds light not only on virulence and pathology, but also leads to a greater understanding of how life works."
One key area of this research focuses on the mechanisms that enable yeasts such as Candida albicans to switch between two different forms. For example, when Candida enters the respiratory tract, the spore-like yeasts germinate and become an elongated, filamentous row of cells. Like other yeasts, they multiply through cell division, or grow as filaments. It is this filamentation that enables Candida's cell walls to bind to the respiratory tract. "This ability to exist in two different forms give fungi a real advantage and flexibility to deal with immune systems," says Wheeler.
Ongoing investigations in Fink's lab of how Candida albicans interacts with immune system cells are enabling labs elsewhere to explore this yeast at the molecular level. Fink's team and other researchers in the field want to determine how the immune system recognizes and defends against different fungal pathogens and explore the mechanisms that enable these pathogens to resist anti-fungal drugs. A better understanding of these processes could help researchers develop more accurate and effective drugs to contain them.
As it generates new knowledge, this research also may spin off new technologies. Work by Wheeler and Fink on Saccharomyces could lead to a number of beneficial clinical applications. For example, Wheeler notes that a drug combining Saccharomyces and a bacterium found in yogurt called lactobacillus could be used as a probiotic that restores a healthy balance of intestinal microbes. The drug would thereby decrease the severity and duration of diarrhea associated with antibiotic use. In addition, he says, Saccharomyces may be employed as a vaccine delivery vector.
Two other potential applications are in the pipeline. Two years ago, Whitehead postdoctoral fellow Mike Lorenz identified a metabolic pathway that's fungal-specific and required for infection. The Institute has applied for a patent to help develop novel antifungal drugs that target specific fungi. Meanwhile, another postdoctoral fellow, Todd Reynolds, has developed Saccharomyces as a model for understanding the formation of biofilms, or communities of microorganisms that attach to a solid surface. Groups of yeast cells that tend to be more resistant to anti-fungal drugs, fungal biofilms, are potentially a major cause of untreatable fungal infections.
And these ideas only skim the surface. As researchers learn more about pathogenic fungi and yeast, more questions are bound to arise, the answers to which could offer a larger arsenal against the disease-causing agents.
The research was supported by the National Institutes of Health. Robert T. Wheeler is a Burroughs Wellcome Fellow of the Life Science Research Foundation.
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