Role of Amino Acid Metabolism in the Virulence of Human Pathogenic Fungi

Abstract

Purpose of the Review The success of Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans as fungal pathogens depends on their rapid adaptation to host microenvironments, through metabolic remodeling, stress resistance, and expression of virulence determinants. Amino acids represent an abundant nitrogen and carbon source within the host; however, their acquisition by fungi is a very complex process that interconnects several sensory and uptake systems and downstream pathways. In this review, we will summarize the current knowledge concerning this topic, identify gaps or discrepancies, and discuss future research directions. Recent Findings Aside from supporting basic cellular functions, the utilization of many amino acids has a direct effect on fungal pathogenicity by triggering key virulence traits, including hyphal morphogenesis and biofilm growth in C. albicans, capsule formation in C. neoformans, and melanization in A. fumigatus. Summary Although many components of amino acid sensing and metabolism are fungal specific, their importance in infection and potential as candidates for antifungal drug development require further investigation.

Metabolic profiling of Candida clinical isolates of different species and infection sources

“…In relation to biofilm formation, we confirmed the importance of amino acids in biofilm growth, as demonstrated by the higher concentrations of glutamate and lysine in the intracellular compartment of the strongest producer strains 51 .…”

“…These data, indeed, showed how the metabolomic analysis by 1 H-NMR is effective at identifying Candida species and even subgroups. Over again, some amino acids contributed to the differentiation among the groups which are not only related to primary metabolism but also to fungal virulence 51 . Moreover, we found specific metabolic fingerprints associated with different Candida virulence-associated features, such as the ability to form biofilm and the antifungal resistance.…”

“…These data, indeed, showed how the metabolomic analysis by 1 H-NMR is effective at identifying Candida species and even subgroups. Over again, some amino acids contributed to the differentiation among the groups which are not only related to primary metabolism but also to fungal virulence 51 .…”

“…In addition to serve as an alternative carbon source, trehalose has a critical role in the morphogenesis and response to fungal stress, especially dehydration, thermal and oxidative stress 48 – 50 . Amino acids are not only cell signaling molecules but are also important in fungal virulence as regulators of gene expression, morphogenesis and biofilm growth, key precursors for syntheses of hormones and low-molecular weight nitrogenous substances with enormous biological importance 51 , 52 . Previous studies also suggested the role of proline in reducing the production of reactive oxygen species in the mitochondria 53 .…”

Multimodal Role of Amino Acids in Microbial Control and Drug Development

“…Despite being able to biosynthesise amino acids, fungi have also evolved certain mechanisms such as nitrogen catabolic repression (NCR), transceptor-mediated amino acid sensing, Ssy1-Ptr3-Ssy5 (SPS) and target of rapamycin (TOR) pathway to monitor and use the amino acids present in the environment [44]. SPS is used to sense and uptake exogenous amino acids and TOR serves as a sensory system to monitor intracellular amino acids [45].…”