Insights Into Histoplasma capsulatum Behavior on Zinc Deprivation

Abstract

Histoplasma capsulatum is a thermodimorphic fungus that causes histoplasmosis, a mycosis of global incidence. The disease is prevalent in temperate and tropical regions such as North America, South America, Europe, and Asia. It is known that during infection macrophages restrict Zn availability to H. capsulatum as a microbicidal mechanism. In this way the present work aimed to study the response of H. capsulatum to zinc deprivation. In silico analyses showed that H. capsulatum has eight genes related to zinc homeostasis ranging from transcription factors to CDF and ZIP family transporters. The transcriptional levels of ZAP1, ZRT1, and ZRT2 were induced under zinc-limiting conditions. The decrease in Zn availability increases fungicidal macrophage activity. Proteomics analysis during zinc deprivation at 24 and 48 h showed 265 proteins differentially expressed at 24 h and 68 at 48 h. Proteins related to energy production pathways, oxidative stress, and cell wall remodeling were regulated. The data also suggested that low metal availability increases the chitin and glycan content in fungal cell wall that results in smoother cell surface. Metal restriction also induces oxidative stress triggered, at least in part, by reduction in pyridoxin synthesis.

Nutritional immunity: targeting fungal zinc homeostasis

“…Interestingly, metabolic profile showed that glycolysis of glucose (fructose-6-phosphate) induces the biosynthesis of glycan and chitin in the cell wall. These results suggest that low metal availability increases the chitin and glycan content in fungal cell wall (Assuncao et al, 2020) a mechanism that has not been shown in yeast and other fungi (North et al, 2012;Wang et al, 2018). Data from the study also suggested that Zn 2þ restriction could trigger oxidative stress, a mechanism shown to be involved in excess Zn 2þ toxicity in yeast.…”

“…The genes included the transcription factor, Zap1 and members of CDF and ZIP family transporters. The transcriptional levels of ZRT1, ZRT2 and ZAP1 were induced in Zn 2þ depleted environment (Assuncao et al, 2020). Proteomics analysis of cells grown in Zn 2þ depleted environment at 24 h and 48 h showed 265 differentially expressed proteins.…”

Global Molecular Response of Paracoccidioides brasiliensis to Zinc Deprivation: Analyses at Transcript, Protein and MicroRNA Levels

“…To evaluate the sensitivity of the fungus P. brasiliensis to limiting zinc conditions, the growth and cell viability of yeast cells in zinc scarcity were evaluated. The results showed that zinc scarcity imposed by up to 200 µM DTPA did not significantly affect fungal viability, as shown in the dimorphic pathogenic fungus Histoplasma capsulatum [ 65 ]. Thus, P. brasiliensis harbors efficient mechanisms to support survival and growth in a Zn-limiting condition.…”

Key thermally dimorphic fungal pathogens: shaping host immunity

“…The host environment can also influence the chitin cell wall content, as shown recently for Histoplasma spp. [ 47 ]. Here Assunção et al demonstrate that low zinc availability in macrophages increases the chitin and glycan content in fungal cell wall.…”

“…The host environment can also influence the chitin cell wall content, as shown recently for Histoplasma spp. [47].…”