Research from the Lancet

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Antifungal drug resistance of pathogenic fungi

Dimitrios P Kontoyiannis, E

Lancet 2002; 359: 1135-44

Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M D Cancer Center, Houston, TX 77030, USA (D P Kontoyiannis FACP); and the College of Pharmacy, University of Houston, Houston, TX (R E PharmD)

Correspondence to: Dr Dimitrios P Kontoyiannis (e-mail:dkontoyi@...)

Pathogenic fungi have many complex mechanisms of resistance to antifungal drugs. Information about the clinical, cellular, and molecular factors contributing to antifungal-drug resistance continues to accumulate. We critically review the diagnosis, epidemiology, and mechanisms of antifungal drug resistance of pathogenic fungi. Better understanding of this resistance should assist in developing better detection strategies for preventing and treating refractory mycoses in the future.

Virulence factor identified for Histoplasma capsulatum

A team of US researchers have identified a candidate virulence factor for the fungal pathogen Histoplasma capsulatum--a major cause of respiratory and systemic disease. "Ours is the first study to use molecular genetics to show that a secreted calcium-binding protein (CBP) is required for H capsulatum parasitism of macrophages and virulence in mice", says Goldman (Washington University, St Louis, MO, USA). H capsulatum is a dymorphic fungus--it can exist as either a mould or a yeast. It lives in the soil as a mould, but when inhaled into the respiratory system the higher temperature converts it to a yeast, its parasitic form. Macrophages engulf the yeast, but are unable to kill them.

Goldman's team focused on the gene that codes for the CBP because it is inactive in the soil-dwelling mould, but is switched on in the pathogenic yeast. Using a novel genetic technique, the researchers knocked out the CBP gene, producing mutant H capsulatum that did not grow well in macrophages and were unable to kill them. Importantly, when inhaled by mice, the mutant fungus was a thousand times less effective in infecting the lungs (Science 2000; 290: 1368-72).

Exactly why CBP is essential for H capsulatum survival is unknown. One possibility is that CBP may inhibit the acidification, and thus function, of endosomes. According to Bruce Klein (University of Winsconsin-Madison, Madison, WI, USA), "if this hypothesis is correct, then CBP would connect two key cellular events--the regulation of pH and calcium ion concentration --making it clear why CBP is so crucial to intracellular survival of Histoplasma yeast".

Butcher