Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Sun, Tianshu; Ju, Xingrong; Gao, Huiling; Wang, Tao; Thiele, Dennis J.; Li, Jiayi; Wang, Zhan-You; Ding, Chen

doi:10.1038/ncomms6550

Cited by 80 publications

(116 citation statements)

References 57 publications

(100 reference statements)

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“…Cu is an effective antimicrobial agent (16)(17)(18), and during infection host elevations in Cu can occur in macrophages (13,14) and in certain tissues (e.g., the lung during pulmonary invasion by C. neoformans) (11). However, not all tissues may exhibit a heightened Cu response as has been reported for the brain during C. neoformans invasion (19,20). With C. albicans infection, the Cu response of the host is poorly understood.…”

mentioning

confidence: 99%

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

Gleason

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

146

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Copper is both an essential nutrient and potentially toxic metal, and during infection the host can exploit Cu in the control of pathogen growth. Here we describe a clever adaptation to Cu taken by the human fungal pathogen Candida albicans. In laboratory cultures with abundant Cu, C. albicans expresses a Cu-requiring form of superoxide dismutase (Sod1) in the cytosol; but when Cu levels decline, cells switch to an alternative Mn-requiring Sod3. This toggling between Cu- and Mn-SODs is controlled by the Cu-sensing regulator Mac1 and ensures that C. albicans maintains constant SOD activity for cytosolic antioxidant protection despite fluctuating Cu. This response to Cu is initiated during C. albicans invasion of the host where the yeast is exposed to wide variations in Cu. In a murine model of disseminated candidiasis, serum Cu was seen to progressively rise over the course of infection, but this heightened Cu response was not mirrored in host tissue. The kidney that serves as the major site of fungal infection showed an initial rise in Cu, followed by a decline in the metal. C. albicans adjusted its cytosolic SODs accordingly and expressed Cu-Sod1 at early stages of infection, followed by induction of Mn-Sod3 and increases in expression of CTR1 for Cu uptake. Together, these studies demonstrate that fungal infection triggers marked fluctuations in host Cu and C. albicans readily adapts by modulating Cu uptake and by exchanging metal cofactors for antioxidant SODs.

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confidence: 99%

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

Gleason

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

146

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“…In contrast to other trace elements, work over the past decade demonstrates that host innate immune cells concentrate Cu in the vicinity of invading pathogens, as a means to exploit Cu toxicity and enhance microbial killing (16,26). Moreover, for C. neoformans, and perhaps other fungal pathogens, hosts use both Cu compartmentalization and Cu sequestration, in distinct infectious niches, to subjugate pathogenesis (27,28).…”

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confidence: 99%

Copper at the Fungal Pathogen-Host Axis

García-Santamarina

Thiele

2015

Journal of Biological Chemistry

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Fungal infections are responsible for millions of human deaths annually. Copper, an essential but toxic trace element, plays an important role at the host-pathogen axis during infection. In this review, we describe how the host uses either Cu compartmentalization within innate immune cells or Cu sequestration in other infected host niches such as in the brain to combat fungal infections. We explore Cu toxicity mechanisms and the Cu homeostasis machinery that fungal pathogens bring into play to succeed in establishing an infection. Finally, we address recent approaches that manipulate Cu-dependent processes at the host-pathogen axis for antifungal drug development.

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“…The role of CTR4 in the virulence of C. neoformans remains puzzling, as inconsistent results have been obtained by different studies (Waterman et al 2012;Sun et al 2014). Thus, we carried out virulence testing for the H99, ctr4D and the complemented strains in mouse cryptococcosis models.…”

Section: Critical Roles Of Ctr4 In Extreme Temperaturesmentioning

confidence: 96%

“…Surprisingly, conflicting observations have been reported regarding its role in the virulence of C. neoformans (Waterman et al 2012;Sun et al 2014). Thus, we decided to make a deletion mutant of CTR4, attempting to clarify this issue and to gain a better understanding of Ctr4-mediated physiological processes as a copper transporter.…”

Section: Introductionmentioning

confidence: 96%

“…High-affinity copper uptake is mediated by two plasma membrane transporters encoded by CTR1 and CTR4 in this yeast (Sun et al 2014). Expression of cryptococcal CTR1 or CTR4 both rescues the cell growth defect of a S. cerevisiae ctr1D/ctr3D strain, indicating the independent role of these two copper transporters (Ding et al 2011;Sun et al 2014).…”

Section: Introductionmentioning

confidence: 97%

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Effects of CTR4 deletion on virulence and stress response in Cryptococcus neoformans

Zhang

Zhao

et al. 2016

Antonie van Leeuwenhoek

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Roles of the high-affinity copper transporter Ctr4 in the virulence of Cryptococcus neoformans remain to be fully determined. Here we demonstrate that Ctr4 plays a necessary role in virulence and tolerance to a number of stress conditions. We first observed, with the method of flame atomic absorption spectrometry, that deletion of CTR4 resulted in a significant decrease in intracellular copper level, confirming the role of Ctr4 as a copper transporter in C. neoformans. Furthermore, CTR4 was critical for the yeast to survive at both elevated and low temperatures, as the growth rate of the ctr4Δ mutant at 4 and 37 °C was significantly decreased. The mutant ctr4Δ also exhibited hypersensitivity to osmotic stress imposed by 2 M NaCl or KCl, indicating the possible crosstalk of Ctr4 with the HOG signalling pathway. Moreover, cell wall and plasma membrane integrity appeared to be impaired in the ctr4Δ strain. The virulence of ctr4Δ in two mouse cryptococcosis models was remarkably reduced either via an intranasal or intravenous inoculation. Our work confirms the roles of Ctr4 in virulence and copper homeostasis as well as other additional novel functions.

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Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

Cited by 80 publications

References 57 publications

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

Copper at the Fungal Pathogen-Host Axis

Effects of CTR4 deletion on virulence and stress response in Cryptococcus neoformans

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