José Antonio Calera

Regulation of zinc homeostasis and virulence in fungal pathogens

The tissues and organs of living organisms including humans are very hostile environments that cannot be invaded by non-pathogenic microorganisms. In contrast, cellular microbial pathogens have developed adaptations that allow them to grow over and invade the tissues of susceptible animal host and cause disease. One of these adaptations enables to all of them to obtain efficiently from the host all nutrients that they need to grow on mucous membranes or within tissues, including zinc. However, in living tissues the bioavailability of Zn2+ free ions is extremely low as they are tightly bound to proteins. Thus, pathogens have developed mechanisms to scavenge and uptake this essential metal from host tissues.

In our laboratory we use as a model the human fungal pathogen Aspergillus fumigatus, which causes one of the most aggressive and fatal fungal infectious diseases called invasive pulmonary aspergillosis (IPA), to investigate the molecular mechanisms used by eukaryotic pathogens to overcome the host defenses and invade host tissues. More precisely, our main goal is to understand the regulatory mechanism of zinc homeostasis in A. fumigatus, how zinc homeostasis is influenced either directly or indirectly by other environmental factors and the consequences that would have any alteration of zinc homeostasis on the physiology and virulence of this fungal pathogen.

The work done in our laboratory until now has resulted in the identification of the main transcriptional regulator of zinc homeostasis in A. fumigatus (ZafA) and its role in the regulation of the expression at the transcriptional level and virulence. In addition, zinc homeostasis in A. fumigatus is also strongly influenced by the environmental pH such that the expression of zinc transporters encoding genes such as zrfA and zrfB are required for fungal growth on acidic zinc-limiting media whereas that of the zrfC gene was essential for fungal growth in alkaline and extremely zinc-limiting media (Fig. 1A). Interestingly, survival, histopathologic and immunocytochemical studies conduced in both leucopenic and non-leucopenic murine models of IPA have revealed the different relevance of each gene in virulence (Fig. 1B).

Our research will contribute to understand better the mechanisms used by fungal pathogens to scavenge and obtain zinc from the host, grow within it and cause disease. Besides, all knowledge arising from our investigations will ultimately contribute to implement new therapies against IPA based on interfering with fungal zinc uptake from the host.

(A) Growth of A. fumigatus mutant strains with defects in zinc uptake from acidic and alkaline zinc-limiting media. (B) A wild-type A. fumigatus strain (wt) and a ΔzrfC mutant growing within the lungs of leucopenic mice. Note that the fungal growth capacity of the wt strain is much larger than that of a fungal strain whose zrfC gene has been deleted.

Group members
José Antonio Calera Abad Associate Professor (USAL)
Fernando Leal Associate Professor (USAL)
Rocío Vicentefranqueira Rodríguez Postdoctoral
Héctor Toledo Porteros PhD Student
Recent publications
Amich J, Calera J A. (2014).
Zinc acquisition: a key aspect in Aspergillus fumigatus virulence.
Mycopathologia. 178:379-385.
Amich J, Vicentefranqueira R, Mellado E, Ruiz-Carmuega A, Leal F, Calera JA. (2014).
The ZrfC alkaline zinc transporter is required forAspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin.
Cell Microbiol. 16:548-564.
Amich J, Vicentefranqueira R, Leal F, Calera JA. (2010).
Aspergillus fumigatus survival in alkaline and extreme zinc-limiting environments relies on the induction of a zinc homeostasis system encoded by the zrfC and aspf2 genes.
Eukaryot Cell. 9:424-437.
Amich J, Leal F, Calera JA. (2009).
Repression of the acid ZrfA/ZrfB zinc-uptake system of Aspergillus fumigatus mediated by PacC under neutral, zinc-limiting conditions.
Int Microbiol. 12:39-47.
Moreno MA, Ibrahim-Granet O, Vicentefranqueira R, Amich J, Ave P, Leal F, Latge JP, Calera JA. (2007).
The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence.
Mol Microbiol. 64:1182-1197.
Research grants
MINECO: SAF2014-48382-R
Links of interest