Biphasic zinc compartmentalisation in a human fungal pathogen.

Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans. Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C. albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2-null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus, suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C. albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C. albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C. albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C. albicans. Here we show that, unlike in Saccharomyces cerevisiae, C. albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo. In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation.

Nutritional Immunity and Fungal Pathogenesis: The Struggle for Micronutrients at the Host-Pathogen Interface.

All living organisms require certain micronutrients such as iron, zinc, manganese and copper for cellular function and growth. For human pathogens however, the maintenance of metal ion homeostasis is particularly challenging. This is because the mammalian host actively enforces extremes of micronutrient availability on potential microbial invaders-processes collectively termed nutritional immunity. The role of iron sequestration in controlling microbial infections is well established and, more recently, the importance of other metals including zinc, manganese and copper has been recognised. In this chapter, we explore the nutritional immune mechanisms that defend the human body against fungal infections and the strategies that these important pathogens exploit to counteract nutritional immunity and thrive in the infected host.

Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens.

The ability of pathogenic microorganisms to assimilate sufficient nutrients for growth within their hosts is a fundamental requirement for pathogenicity. However, certain trace nutrients, including iron, zinc and manganese, are actively withheld from invading pathogens in a process called nutritional immunity. Therefore, successful pathogenic species must have evolved specialized mechanisms in order to adapt to the nutritionally restrictive environment of the host and cause disease. In this review, we discuss recent advances which have been made in our understanding of fungal iron and zinc acquisition strategies and nutritional immunity against fungal infections, and explore the mechanisms of micronutrient uptake by human pathogenic fungi.

Does the relation between volunteering and well-being vary with health and age?

Previous studies have established a positive association between organizational volunteering and well-being. In the current study, we examined whether the relations between organizational volunteering and positive affect, negative affect, and resilience are modified by respondents' age and number of chronic health conditions. This study used cross-sectional data from the 2008 Arizona Health Survey of residents 18 years old and older (N = 4,161). Multiple regression analyses provided no support for the hypothesis that age moderates the association between volunteer status and positive affect, negative affect, and resilience. In contrast, there was a significant (p < .05) interaction between volunteer status and chronic health conditions on positive affect and resilience. Consistent with the compensatory hypothesis, as number of chronic health conditions increased, the relations between volunteering and positive affect and resilience scores increased. Implications of these findings for increasing volunteering among adults with multiple chronic health conditions are discussed.

Testing gender effects on the mechanisms explaining the association between post-traumatic stress symptoms and substance use frequency.

The present study examines gender differences in the mechanisms that explain the association between PTSD symptoms and substance use frequency in a sample of 182 urban substance users. Specifically, the current study examined gender differences in the role of two potential explanatory variables, namely, difficulties controlling impulsive behavior when distressed (IMP), and a lack of emotional awareness and clarity (AW/CLAR). Multiple-group path modeling (across males and females) was used to examine gender differences in the path coefficients from PTSD symptoms to IMP and AW/CLAR, and from these latter variables to drug use frequency. Results indicated that PTSD symptoms were associated with IMP and AW/CLAR, and these path coefficients did not vary by gender. However, gender differences emerged when considering the path coefficients from AW/CLAR and IMP to substance use frequency. Specifically, for women, the association between PTSD and substance use was partially explained by IMP, whereas for men, the association between PTSD and substance use was partially explained by AW/CLAR. The current study is the first to examine gender differences in mechanisms accounting for the association between PTSD and substance use frequency, and these results also support the value and importance of examining gender differences in mechanisms underlying PTSD-SUD comorbidity.