Alterations of Zinc Homeostasis in Response to Cryptococcus Neoformans in a Murine Macrophage Cell Line

Abstract

These findings suggest that macrophages may exhibit zinc depletion in response to C. neoformans infection.

Transcriptional Analysis Allows Genome Reannotation and Reveals that Cryptococcus gattii VGII Undergoes Nutrient Restriction during Infection

“…A growing body of evidence suggests that cryptococcal cells undergo nutritional limitations in infection conditions and must, therefore, express nutrient uptake transporters on the cell surface in order to survive the harsh environment of the infection milieu [ 16 , 33 , 34 , 35 ]. Therefore, we determined the presence of transporter-coding transcripts among the most abundant genes.…”

Modulation of Zinc Homeostasis in Acanthamoeba castellanii as a Possible Antifungal Strategy against Cryptococcus gattii

“…We recently provided evidence that C. neoformans cells experience zinc deprivation inside macrophages ( Dos Santos et al, 2017 ). The main mechanism by which cryptococcal cells acquire zinc is through activity of the Zip1 protein ( Schneider et al, 2015 ; Do et al, 2016 ).…”

“…Zinc restriction has already been characterized for macrophages infected with the fungal pathogens H. capsulatum and C. neoformans . The mechanism by which zinc levels were reduced in macrophages was shown to be dependent on the activity of zinc transporters of the ZnT family ( Winters et al, 2010 ; Subramanian Vignesh et al, 2013a ; Dos Santos et al, 2017 ). At least four lines of evidence allowed us to conclude that amoebae expose cryptococcal cells to a nutritional immunity-like mechanism: (i) assays employing the zinc fluorescent probe ZinPyr-1 revealed that labile zinc levels were reduced in A. castellanii cells exposed to C. gattii ; (ii) transcription levels of some A. castellanii ZnT-coding genes were highly modulated by the presence of cryptococcal cells; (iii) C. gattii cells with reduced growth in zinc-limiting conditions experienced impaired proliferation inside amoeba cells; and (iv) addition of extracellular zinc enhanced intracellular survival of C. gattii cells lacking the major zinc transporter.…”

“…Macrophages modulate the expression of zinc transporters of the ZnT family and metallothioneins in order to reduce zinc bioavailability for H. capsulatum ( Subramanian Vignesh et al, 2013a ) and C. gattii ( Dos Santos et al, 2017 ). Among such transporters, ZnT4 and ZnT7 are assumed to play a direct role in zinc compartmentalization, as the transcript levels of such genes were regulated in macrophages infected with fungal pathogens ( Subramanian Vignesh et al, 2013a ; Dos Santos et al, 2017 ). These proteins are associated with the Golgi apparatus ( Subramanian Vignesh et al, 2013b ; Subramanian Vignesh and Deepe, 2016 ).…”

“…We previously described that correct zinc metabolism regulation is important for C. gattii virulence in murine models of cryptococcosis ( Schneider et al, 2012 , 2015 ), reinforcing the importance of zinc uptake for proper cell metabolism. In addition, J774.A1 macrophages are also capable of decreasing zinc levels in response to C. neoformans infection ( Dos Santos et al, 2017 ). This is similar to phenotypes observed for macrophages infected with different pathogens such as Histoplasma capsulatum ( Haase, 2013 ) and Candida albicans ( Lorenz et al, 2004 ; Crawford and Wilson, 2015 ).…”