Research Article: Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus

Date Published: August 29, 2013

Publisher: Public Library of Science

Author(s): Jorge Amich, Lukas Schafferer, Hubertus Haas, Sven Krappmann, Marta Feldmesser.

http://doi.org/10.1371/journal.ppat.1003573

Abstract

Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

Partial Text

Aspergillus fumigatus is an opportunistic fungal pathogen that may cause invasive infections in immunocompromised patients. During the last decades the incidence rate of invasive pulmonary aspergillosis (IPA), the most severe infection caused by this mould [1], has dramatically increased which mainly results from the rise in immune-suppressive medical therapies. Furthermore, IPA is accompanied by a high mortality rate which may reach up to 90% depending on the immune status of the host [2], [3], [4]. This pronounced lethality is primarily attributed to the relative inefficiency of current chemotherapies [5], which are based on disrupting the integrity of the fungal cell membrane or cell wall [6]. Therefore, an urgent need to identify targets for the development of novel antifungal substances is evident.

Fulfillment of nutritional and metabolic requirements is essential for all pathogenic microorganisms to be able to grow inside the host and, thus, to cause infection and disease [7]. For opportunistic fungal pathogens this is highly relevant, since these commonly lack specific virulence factors that would provoke host damage [9]. In recent years more and more evidence has been provided that fungal metabolism is a critical component of fungal virulence [65]. Accordingly, it has been proposed that based on this knowledge novel antifungal targets might be identified [10].

 

Source:

http://doi.org/10.1371/journal.ppat.1003573

 

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