Fungal Pathogens: Getting to “C-u”

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Science Translational Medicine  31 Oct 2012:
Vol. 4, Issue 158, pp. 158ec196
DOI: 10.1126/scitranslmed.3005204

Several fungal pathogens can cause meningitis, as chillingly illustrated by the current US outbreak of meningitis attributed to tainted steroid injections contaminated by the fungal pathogen Exserohilum rostratum. Fungal infections of the central nervous system are acquired from environmental sources by inhalation or via skin wounds, or in the current outbreak by direct injection of a contaminated medication into the spinal area. Shedding light on the pathogenesis of meningitis-causing fungi, Waterman and colleagues show that uptake of copper (Cu) is an important factor in the virulence of the fungus Cryptococcus neoformans.

The authors first showed the importance of copper for growth of C. neoformans in vitro and then demonstrated the crucial role played by the copper transporter protein CTR4. An isogenic mutant that lacked CTR4 showed impaired growth when copper was limiting. This CTR4 mutant infected a murine macrophage cell line roughly 3-fold less efficiently than wild-type C. neoformans. When mice were exposed to this same CTR4 mutant through the nose or bloodstream, they did not become infected and showed 100% survival compared to almost no survival among mice infected with the wild-type fungal strain.

Using a fluorescent protein reporter, the authors were able to demonstrate that CTR4 localized to the periphery of C. neoformans cells in culture, in mouse macrophages, and in lung cells recovered from infected mice. Interrogation of a CTR4 reporter during infection showed substantial induction of CTR4 expression in C. neoformans in the mouse lung. This apparent need for C. neoformans to increase copper uptake in the lung suggests that the lung is a copper-depleted environment or that C. neoformans requires additional copper to infect the lung. Both possibilities mean that successful infection may depend upon C. neoformans achieving copper homeostasis.

Fungal meningitis is not known to be transmitted from person to person. The greatest risk factors are inhalation (primarily from exposure to certain soils) and having a weakened immune system. Although the authors point out that this study in a mouse model may not fully translate to human fungal infections, the new findings reveal a key role for copper uptake during fungal pathogenesis. Future work will need to determine whether combining antifungal medications with copper chelation in vivo could improve treatment of fungal infections in human patients.

S. R. Waterman et al., Role of CTR4 in the virulence of cryptococcus neoformans. MBio e00285-12 (2012) [Full Text]

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