Overview of carbon and nitrogen catabolite metabolism in the virulence of human pathogenic fungi

Abstract

SummaryIt is estimated that fungal infections, caused most commonly by Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, result in more deaths annually than malaria or tuberculosis. It has long been hypothesized the fungal metabolism plays a critical role in virulence though specific nutrient sources utilized by human pathogenic fungi in vivo has remained enigmatic. However, the metabolic utilisation of preferred carbon and nitrogen sources, encountered in a host niche-dependent manner, is known as carbon catabolite and nitrogen catabolite repression (CCR, NCR), and has been shown to be important for virulence. Several sensory and uptake systems exist, including carbon and nitrogen sourcespecific sensors and transporters, that allow scavenging of preferred nutrient sources. Subsequent metabolic utilisation is governed by transcription factors, whose functions and essentiality differ between fungal species. Furthermore, additional factors exist that contribute to the implementation of CCR and NCR. The role of the CCR and NCR-related factors in virulence varies greatly between fungal species and a substantial gap in knowledge exists regarding specific pathways. Further elucidation of carbon and nitrogen metabolism mechanisms is therefore required in a fungal species-and animal model-specific manner in order to screen for targets that are potential candidates for anti-fungal drug development.

Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality

“…Carbon metabolism and its regulation are central to the pathogenic capability of C. albicans. Carbon metabolic genes undergo dynamic expression changes in numerous colonization and infection models, and defects in carbon metabolism or its regulation disrupt the ability to colonize the GI tract, duel with macrophages and other host cells, and infect host tissues [2,4]. Here we have extended our understanding of one major carbon regulatory pathway, the Snf1 pathway.…”

“…It is tightly controlled in most organisms to enable optimal use of diverse carbon sources. The ability to adapt to changing carbon sources is especially important for commensal and pathogenic microbes because microbial competitors and host factors can cause dynamic changes in the spectrum of carbon compounds available [1,2].…”

“…It exists primarily as a commensal resident of the GI and GU tracts of humans and other warm-blooded animals. However, upon dysbiosis of the host environment it can cause infections that include oropharyngeal candidiasis, cutaneous candidiasis, vaginal candidiasis, and systematic or intra-abdominal candidiasis stemming from colonization of the patient's own GI tract [2,3]. The ability of C. albicans to cause infection of diverse tissues and body sites depends upon its ability to regulate the utilization of diverse carbon sources [4].…”

“…One form of metabolic regulation is called "glucose repression" or "carbon catabolite repression" [2,4]. In the presence of glucose, a preferred carbon source, expression of genes for use of alternative (i.e., non-glucose) carbon sources is repressed.…”

The bZIP transcription factor VdAtf1 regulates virulence by mediating nitrogen metabolism in Verticillium dahliae

“…Fungi have developed sophisticated mechanisms for nitrogen acquisition and there are preferred nitrogen sources such as ammonium and glutamine that promote fungal fitness, survival and virulence within the host (Ries et al , 2018). In the presence of the preferred nitrogen sources such as ammonium (NH 4 + ) and l ‐glutamine, the utilization of alternative nitrogen sources such as nitrate (NO 3 − ) is repressed, which is known as nitrogen catabolite repression (NCR) (Ries et al , 2018).…”