Ambient Availability of Amino Acids, Proteins, and Iron Impacts Copper Resistance of Aspergillus fumigatus

Abstract

The transition metals iron and copper are required by virtually all organisms but are toxic in excess. Acquisition of both metals and resistance to copper excess have previously been shown to be important for virulence of the most common airborne human mold pathogen, Aspergillus fumigatus. Here we demonstrate that the ambient availability of amino acids and proteins increases the copper resistance of A. fumigatus wild type and particularly of the ΔcrpA mutant that lacks export-mediated copper detoxification. The highest-protecting activity was found for L-histidine followed by L-asparagine, L-aspartate, L-serine, L-threonine, and L-tyrosine. Other amino acids and proteins also displayed significant but lower protection. The protecting activity of non-proteinogenic D-histidine, L-histidine-mediated growth inhibition in the absence of high-affinity copper uptake, determination of cellular metal contents, and expression analysis of copper-regulated genes suggested that histidine inhibits low-affinity but not high-affinity copper acquisition by extracellular copper complexation. An increase in the cellular copper content was found to be accompanied by an increase in the iron content, and, in agreement, iron starvation increased copper susceptibility, which underlines the importance of cellular metal balancing. Due to the role of iron and copper in nutritional immunity, these findings are likely to play an important role in the host niche.

Key Role of Vegetation Cover in Alleviating Microplastic-Enhanced Carbon Emissions

“…Multiple “favorable amino acids” were examined in Figure b,c and Supplementary Figure 23, and their significant enrichment suggested that metabolism of intermediates (3-phosphoglycerate, pyruvate, phosphoenolpyruvate, erythrose-4-phosphate, 2-oxoglutarate and oxaloacetate) from glycolysis, the citric acid cycle, and the pentose phosphate pathway were upregulated (especially in shrub soils with superior resistance and resilience compared to their grass counterparts) (Supplementary Table 14). Specifically, for amino acids negatively correlated with enzymes, Met was not considered due to the low detection limit, whereas the increased His in shrub soil may be due to the ambient availability (highest protecting activity compared to other amino acids) of His increasing cellular tolerance to PSMPs . These results further emphasize the advantages of shrub soils in enhancing the metabolic effects.…”

“…82 Specifically, for amino acids negatively correlated with enzymes, Met was not considered due to the low detection limit, whereas the increased His in shrub soil may be due to the ambient availability (highest protecting activity compared to other amino acids) of His increasing cellular tolerance to PSMPs. 83 These results further emphasize the advantages of shrub soils in enhancing the metabolic effects.…”

Functional characterization of genes encoding cadmium pumping P 1B -type ATPases in Aspergillus fumigatus and Aspergillus nidulans

“…Emerging data show that there is a tight association between the metabolism of different transition metals in fungi, in addition to the copper dependence of iron uptake via the reductive iron assimilation pathway, which has been observed in several fungi ( 20 , 25 , 33 ). It has also been shown that an increase in intracellular copper levels can elevate the iron content in A. fumigatus cells ( 34 ). Iron availability also regulates zinc metabolism mediated by the transcription factor ZafA ( 35 ), and in line with this, iron starvation has been shown to upregulate the vacuolar zinc transporter ZrcA (important in removing excess zinc from cytosol) and downregulate the zinc importer ZrpB in A. fumigatus ( 36 ).…”

“…Macrophages secrete Cu 2+ into the phagosomes to kill the ingested microbes ( 13 , 14 ). Moreover, iron-limited conditions of phagosomes and superoxide anion secreted into the phagosomes enhance copper toxicity further ( 34 ). Microbes may also suffer from iron/zinc overload when they escape from phagosomes to the cytosol ( 11 ).…”

“…3 and 4 ; Tables 1 and 2 ) probably indirectly through the secretion of Cu 2+ and/or Zn 2+ . Thus, these cadmium pumps may protect cells from dangerous metal ions they can pump (which are not limited to Cd 2+ ) and may even reduce the toxicity of those they cannot pump due to the tight coupling of the metabolism of different metal ions ( 33 – 36 ). These properties of the two ATPases can contribute to the virulence of both A. nidulans ( 3 ) and A. fumigatus ( 1 ) and therefore represent potential targets for antifungal therapy.…”