Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans

Abstract

Echinocandins such as caspofungin are front line antifungal drugs that compromise β-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by up-regulation of chitin synthesis, thereby sustaining cell wall integrity. When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a sub-population of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable super high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway.

Transcriptional Response of Candida albicans to Nanostructured Surfaces Provides Insight into Cellular Rupture and Antifungal Drug Sensitization

“…Previous work has shown that mechanical challenges to yeast cells result in the activation of specific signature transcriptional targets of signal transduction pathways such as the cell wall integrity pathway; , however, we did not observe the expression of genes assocaited with any canonical stress-activated signaling pathway in the NSS response. The NSS response transcriptome enzyme contained genes with several metabolic pathways: ten metabolic pathways have genes that were up-regulated including the genes associated with the tricarboxylic acid (TCA) cycle, whereas genes associated with 14 metabolic pathways including the ergosterol biosynthesis pathway and DNA mismatch repair were down-regulated (Figure A; Tables , ; Supporting Information Table 1).…”

The importance of antimicrobial resistance in medical mycology

“…Time series can be analyzed similarly to experimental evolution experiments and identified mutations can be correlated with clinical data, including changes in the application of antifungal therapies. Evaluating isolates for mutations known to confer drug resistance can establish the prevalence of specific mutations, however unstable changes such as aneuploidy, heteroresistance and physiological adaptations such as cell wall compensation changes can be missed unless drug selection is maintained 40,57 . Examining how these mutations have spread through the population by mapping them to a phylogeny of the isolates, can determine the level of stratification and number of independent resistance emergence of events 47 .…”

Microevolution of clade II isolates ofCandida aurishighlights multifaceted intra-clade heterogeneity in acquiring resistance towards amphotericin B

“…For the chitin synthesis in fungal CW, three pathways are supposed to be cumulatively participating including HOG MAP-kinase pathway, PKC-signalling cascades, and Ca 2+ /Calcineurin-pathway (22). Calcineurin also plays an important role in attenuating the excess synthesis of chitin (23). In the present study, all the adaptors of P-lines display resistance towards FK506, implying activation of calcineurin.…”

“…This highlights the intra-clade differential impact on CW integrity (CWI), and its role therein towards the development of drug resistance mechanisms. Additionally, the MSN4 gene can also act as a chitin synthesis inhibitor (23). This gene was downregulated in all the adaptors of A-line.…”