Nitrogen Source-Dependent Capsule Induction in Human-Pathogenic Cryptococcus Species

Abstract

Cryptococcus neoformans and C. gattii cause meningoencephalitis and are an increasing human health threat. These pathogenic Cryptococcus species are neurotropic and persist in the cerebrospinal fluid (CSF) of the mammalian host during infection. In order to survive in the host, pathogenic fungi must procure nutrients, such as carbon and nitrogen, from the CSF. To enhance our understanding of nutrient acquisition during central nervous system infection by Cryptococcus species, we examined the utilization of nitrogen sources available in CSF. We screened for the growth and capsule production of 817 global environmental and clinical isolates on various sources of nitrogen. Both environmental and clinical strains grew robustly on uric acid, Casamino Acids, creatinine, and asparagine as sole nitrogen sources. Urea induced the greatest magnitude of capsule induction. This induction was greater in Cryptococcus gattii than in C. neoformans. We confirmed the ability of nonpreferred nitrogen sources to increase capsule production in pathogenic species of Cryptococcus. Since urea is metabolized to ammonia and CO 2 (a known signal for capsule induction), we examined urea metabolism mutants for their transcriptional response to urea regarding capsule production. The transcriptional profile of C. neoformans under urea-supplemented conditions revealed both similar and unique responses to other capsule-inducing conditions, including both intra-and extracellular urea utilization. As one of the most abundant nitrogen sources in the CSF, the ability of Cryptococcus to import urea and induce capsule production may substantially aid this yeast's survival and propagation in the host. Cryptococcus neoformans is a pathogenic, basidiomycete yeast responsible for causing meningoencephalitis in immunocompromised individuals. Distributed worldwide, it is the fourth largest infectious disease killer in sub-Saharan Africa as a complication of the AIDS epidemic (1). Because of the mortality and increasing incidence of cryptococcosis, it is imperative that we understand all aspects of this pathogen-host interaction and the methods of C. neoformans survival in an attempt to disrupt them.As with carbon assimilation (2), nitrogen metabolism is fundamentally critical for the survival of fungal pathogens within their plant or animal hosts. For instance, Lau and Hamer reported the influence of nitrogen regulatory elements on the expression of the Magnaporthe grisea pathogenicity gene MPG1 (3). In their study, novel nitrogen regulatory elements NPR1 and NPR2 were shown to be required for expression of MPG1 and the npr1 and npr2 mutant strains were avirulent on barley. Lau and Hamer also demonstrated that the global nitrogen regulatory transcription factor NUT1, a homolog of the Neurospora crassa NIT2 and Aspergillus nidulans areA transcription factor genes, was also partly responsible for MPG1 expression under nitrogen starvation. However, the complexity of the regulation of pathogenicity through nitrogen pathways in fungi is apparent, as strains wit...

Metabolism in Fungal Pathogenesis

“…Similarly, the extracellular ureases of C. neoformans and Cryptococcus gattii (Ure1) degrade urea, which is abundant in the cerebrospinal fluid. The liberated CO 2 acts as a signal to induce capsule formation, a well-studied virulence factor in this fungus (Frazzitta et al 2013).…”

A novel resistance pathway for calcineurin inhibitors in the human pathogenic MucoralesMucor circinelloides

“…How this link is achieved in these fungi remains be elucidated. In C. neoformans , there is evidence that higher expression of an amino acid permease is correlated with the phenotypes regulated by PKA; treatment with urea results in a 27-fold increase of an amino acid permease (CNAG_01118) and increased capsule production that is known to be regulated by PKA (66–68). Our current study investigates the links between calcineurin, amino acid permease, and PKA which could also exist in C. neoformans and possibly other fungi.…”

Diversity and abundance of human‐pathogenic fungi associated with pigeon faeces in urban environments

“…Moreover, there was a positive relationship between green area and the number of both CRF and non‐CRF fungi that can colonize pigeon faeces. These two factors, in combination with evidence that some CRF are better adapted to pigeon faeces than non‐CRF (Litvintseva et al., ; Mantovani, ), may selectively increase the relative abundance of CRF species (Frazzita et al., ; Lee et al., , ; Xue, ). Finally, the density of CRF may decrease with increasing wind speeds, because high wind speed can decrease the level of airborne fungi and thus decrease the number of spores settling on faeces (Guinea et al., ; Hasnain, ).…”

“…Recent studies, however, suggest a more serious health threat appears to be their excrement, which is ubiquitous in urban areas. The chemical composition of pigeon faeces, specifically the availability of nitrogen from uric acid, creates an excellent substrate for fungal spores to propagate, and several studies have shown that pathogenic fungi metabolize faecal compounds during various developmental processes (Frazzita et al., ; Lee, Chow, Morrow, Djordjevic, & Fraser, ; Lee et al., ; Xue, ).…”