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MICROBIOLOGY Worms Teach Lesson on Mechanism of Fungal Infection C. Elegans Model May Reveal Targets in Fungal Battle Plan It may be tiny, tubular, and altogether primitive, but the worm C. elegans has proved surprisingly useful in studying genetic processes that parallel those of humans. Lately, research has shown that the nematode also has something to say about microbial pathogenesis--because it is proving to be susceptible to some of the same infections that humans are. A study in Proceedings of the National Academy of Sciences (online Nov. 15) offers up a C. elegans model of fungal infection, showing that the pathogenic fungus Cryptoccocus neoformans infects worms using some of the same weapons it does in humans. The model may speed the identification of fungal targets on a much larger scale than existing mammalian models. Left, C. elegans feeding on nonpathogenic yeast C. laurenti is the picture of health. The nematode's pharyngeal grinder organ (small white arrows) normally functions to disrupt ingested organisms. Right, when a worm feeds on the pathogenic C. neoformans, the yeast cells accumulate in its bloated gut (red arrows). (Images courtesy of Eleftherios Mylonakis) Elusive Antifungals C. neoformans, a common fungus found in soil and bird droppings, is normally harmless in humans but can cause a relentless infection in immunocompromised patients such as those with HIV/AIDS. Once inhaled, it can make its way into lymphocytes and often migrates to the central nervous system, where it causes meningitis. For patients with AIDS, the threat of fungal infection may require taking antifungal medications indefinitely. In developing countries, where infection rates are on the rise, a lack of available treatments leads to high death rates among those infected. Fungi are trickier to kill than most bacteria--their cells are more like our own, so drugs that work by killing them have toxic side effects. And unlike antibacterials, naturally occurring antifungal substances are uncommon. Eleftherios Mylonakis, HMS instructor in medicine at Massachusetts General Hospital and first author of the study, was frustrated to find in his infectious disease practice that the standard antifungal treatment was developed 30 years ago. If a drug could target fungal virulence factors directly, it might inflict less damage on host cells. However, he pointed out, "There are almost no clear-cut targets." Eleftherios Mylonakis, Frederick Ausubel (above, l to r), and Stephen Calderwood, (below), teamed up to see if the worm C. elegans was susceptible to pathogenic yeast in the same way mammals are. (Mylonakis photo by Steve Gilbert. Calderwood photo by S. Bray) Mylonakis worked with the labs of Frederick Ausubel, HMS professor of genetics, and Stephen Calderwood, HMS professor of medicine (microbiology and molecular genetics), which had teamed up previously to develop a C. elegans model of bacterial pathogenesis (see Focus, Oct. 12, 2001). The worms are normally fed a bacterial diet of E. coli in the laboratory; for a fungal model, the team had to first determine whether yeasts, the experimental fungi, could be ingested by the worms. Yeast cells are much larger than bacteria, so it was possible they might be a bigger bite than the nematodes could swallow. The team let the nematodes feed on a bed of fungi--C. neoformans as well as two other yeasts that are not pathogenic to humans. They found that the C. elegans were able to feed on the harmless strains just fine with no signs of harm. Eating C. neoformans, however, caused the worms to die in a matter of days. Rather than being digested in the primitive gut of the nematodes, the yeast cells had accumulated inside a bloated digestive tract. Seeking a Dopamine Fix To see if similar mechanisms would cause pathology in worms and mammals, the team, in collaboration with Joseph Heitman and John Perfect of Duke University, studied mutant strains of C. neoformans known to cause varying degrees of harm in mouse and rabbit models. They found that these mutations had similar effects on the death rate of C. elegans. One factor that makes C. neoformans more virulent is the production of melanin. The fungus needs dopamine to synthesize melanin, which helps explain why it often flocks to the dopamine-rich brain of humans. Adding dopamine to the bed of yeast that C. elegans fed on also increased the deadliness of C. neoformans in the worms. "You can replicate a situation that we see in the human body and human infection," Ausubel said. The nematodes also yielded an insight that could not have come from mammalian models. A RAS1 signaling pathway has been shown to promote infection in mammals by allowing the fungi to grow in the high temperatures of mammalian bodies. But a ras1-mutant strain, which is less pathogenic in mammalian models, also caused less damage in C. elegans kept at much lower temperatures, suggesting that the pathway has functions other than just temperature control. A C. elegans model could be used to screen for new virulence factors at a much faster rate and larger scale than could be performed in mammalian models--and perhaps uncover more effective drug strategies than the ones currently in use. "Ideally, you could scan the entire genome," Ausubel said. Similarly, the host responses of C. elegans could be studied for insights into how the human innate immune system responds to infection. A group from the Albert Einstein College of Medicine recently showed that C. neoformans can infect amoebae with some of the same strategies it uses to infect human macrophages. Aside from their practicality as disease models, the two approaches also make the case that the pathogenic tricks of fungi developed in response to simpler predators in the natural environment--denizens of the soil like amoebae and C. elegans. "The fascinating thing about this is that it gives us clues as to how virulence factors in microorganisms evolved," said Stuart Levitz, professor of medicine and microbiology at the Boston University School of Medicine and a C. neoformans expert not involved with this study. "It probably was not from interacting with people or mice; the fungus probably gained its ecological niche by evolving virulence factors that allow it to survive in the soil." So it makes sense that even the lowly worm can provide some lofty lessons on human encounters with microorganisms. --Courtney Humphries