Adaptation to iron deficiency in human pathogenic fungi

Iron is an essential micronutrient for virtually all eukaryotic organisms and plays a central role during microbial infections. Invasive fungal diseases are associated with strikingly high rates of mortality, but their impact on human health is usually underestimated. Upon a fungal infection, hosts restrict iron availability in order to limit the growth and virulence of the pathogen. Here, we use two model yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, to delve into the response to iron deficiency of human fungal pathogens, such as Candida glabrata, Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. Fungi possess common and species-specific mechanisms to acquire iron and to control the response to iron limitation. Upon iron scarcity, fungi activate a wide range of elegant strategies to capture and import exogenous iron, mobilize iron from intracellular stores, and modulate their metabolism to economize and prioritize iron utilization. Hence, iron homeostasis genes represent remarkable virulence factors that can be used as targets for the development of novel antifungal treatments.     

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S‐adenosylmethionine, which, after transferring its methyl group, is converted to S‐adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.     

Dynamic optimization reveals alveolar epithelial cells as key mediators of host defense in invasive aspergillosis

Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is an important virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we found that epithelial cells, which have been underappreciated, play a role in fungal clearance and are potent mediators of cytokine release. Both predictions were confirmed by in vitro experiments on established cell lines as well as primary lung cells. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence traits.     

Aspergillus fumigatus: contours of an opportunistic human pathogen

Aspergillus fumigatus is currently the major air‐borne fungal pathogen. It is able to cause several forms of disease in humans of which invasive aspergillosis is the most severe. The high mortality rate of this disease prompts increased efforts to disclose the basic principles of A. fumigatus pathogenicity. According to our current knowledge, A. fumigatus lacks sophisticated virulence traits; it is nevertheless able to establish infection due to its robustness and ability to adapt to a wide range of environmental conditions. This review focuses on two crucial aspects of invasive aspergillosis: (i) properties of A. fumigatus that are relevant during infection and may distinguish it from non‐pathogenic Aspergillus species and (ii) interactions of the pathogen with the innate and adaptive immune systems.     

Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response

Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary infections, termed “aspergilloses,” in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host–pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that an A. fumigatus mutant with low persulfidation levels is more susceptible to host-mediated killing and displays reduced virulence in murine models of infection. Additionally, we found that a single nucleotide polymorphism (SNP) in the human gene encoding cystathionine γ-lyase (CTH) causes a reduction in cellular persulfidation and correlates with a predisposition of hematopoietic stem cell transplant recipients to invasive pulmonary aspergillosis (IPA), as correct levels of persulfidation are required for optimal antifungal activity of recipients’ lung resident host cells. Importantly, the levels of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting a host–pathogen functional correlation and highlighting a potential new therapeutic target for the treatment of aspergillosis.

This study reveals that the post-translational modification persulfidation is important for both fungal virulence and the host antifungal response. The level of persulfidation in the host, which correlates with its antifungal potency, impacts the level required in the fungus to counteract host attack, reflecting a functional correlation. Thus modulating persulfidation may be a promising strategy to target both pathogens and immune responses.     

High osmolarity glycerol response PtcB phosphatase is important for Aspergillus fumigatus virulence

Aspergillus fumigatus is a fungal pathogen that is capable of adapting to different host niches and to avoid host defenses. An enhanced understanding of how, and which, A. fumigatus signal transduction pathways are engaged in the regulation of these processes is essential for the development of improved disease control strategies. Protein phosphatases are central to numerous signal transduction pathways. To comprehend the functions of protein phosphatases in A. fumigatus, 32 phosphatase catalytic subunit encoding genes were identified. We have recognized PtcB as one of the phosphatases involved in the high osmolarity glycerol response (HOG) pathway. The ΔptcB mutant has both increased phosphorylation of the p38 MAPK (SakA) and expression of osmo‐dependent genes. The ΔptcB strain was more sensitive to cell wall damaging agents, had increased chitin and β‐1,3‐glucan, and impaired biofilm formation. The ΔptcB strain was avirulent in a murine model of invasive pulmonary aspergillosis. These results stress the importance of the HOG pathway in the regulation of pathogenicity determinants and virulence in A. fumigatus.     

Current Understanding of HOG-MAPK Pathway in Aspergillus fumigatus

Aspergillus fumigatus is an important opportunistic fungal pathogen that causes lethal systemic invasive aspergillosis. It must be able to adapt to stress in the microenvironment during host invasion and systemic spread. The high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) signaling pathway is a key element that controls adaptation to environmental stress. It plays a critical role in the virulence of several fungal pathogens. In this review, we summarize the current knowledge about the functions of different components of the HOG-MAPK pathway in A. fumigatus through mutant analysis or inferences from the genome annotation, focusing on their roles in adaptation to stress, regulation of infection-related morphogenesis, and effect on virulence. We also briefly compare the functions of the HOG pathway in A. fumigatus with those in the model fungi Saccharomyces cerevisiae and Aspergillus nidulans as well as several other human and plant pathogens including Candida albicans, Cryptococcus neoformans, and Magnaporthe oryzae. The genes described in this review mainly include tcsB, fos1, skn7, sho1, pbs2, and sakA whose deletion mutants have already been established in A. fumigatus. Among them, fos1 has been considered a virulence factor in A. fumigatus, indicating that components of the HOG pathway may be suitable as targets for developing new fungicides. However, quite a few of the genes of this pathway, such as sskA (ssk1), sskB, steC, and downstream regulator genes, are not well characterized. System biology approaches may contribute to a more comprehensive understanding of HOG pathway functions with dynamic details.     

Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification

Reduced supply of the amino acid methionine increases longevity across species through an as yet elusive mechanism. Here, we report that methionine restriction (MetR) extends yeast chronological lifespan in an autophagy-dependent manner. Single deletion of several genes essential for autophagy (ATG5, ATG7 or ATG8) fully abolished the longevity-enhancing capacity of MetR. While pharmacological or genetic inhibition of TOR1 increased lifespan in methionine-prototroph yeast, TOR1 suppression failed to extend the longevity of methionine-restricted yeast cells. Notably, vacuole-acidity was specifically enhanced by MetR, a phenotype that essentially required autophagy. Overexpression of vacuolar ATPase components (Vma1p or Vph2p) suffices to increase chronological lifespan of methionine-prototrophic yeast. In contrast, lifespan extension upon MetR was prevented by inhibition of vacuolar acidity upon disruption of the vacuolar ATPase. In conclusion, autophagy promotes lifespan extension upon MetR and requires the subsequent stimulation of vacuolar acidification, while it is epistatic to the equally autophagy-dependent anti-aging pathway triggered by TOR1 inhibition or deletion.