Calcineurin Is Required forCandida albicansTo Survive Calcium Stress in Serum

Abstract

The calcium-activated protein phosphatase calcineurin plays a critical role in the virulence of Candida albicans. Previous studies demonstrated that calcineurin is not required for the yeast-hypha dimorphic transition, host cell adherence, or host cell injury, which are all established virulence attributes of this organism. Calcineurin is, however, essential for survival in serum and disseminated infection. Here we identify the component of serum that is toxic to calcineurin mutant cells. Proteins, peptides, lipids, and other hydrophobic components were all excluded as essential toxic elements. Upon testing of small molecules present in serum, we discovered that calcineurin protects cells from stress caused by the endogenous levels of calcium ions present in serum. These studies illustrate how calcineurin functions in a calcium homeostatic pathway that enables a common human commensal to survive passage through the hostile environment of the bloodstream to establish deep-seated infections and cause disease.

Calcineurin Controls Drug Tolerance, Hyphal Growth, and Virulence in Candida dubliniensis

“…In other fungal pathogens, including C. neoformans (59), A. fumigatus (73), and Magnaporthe oryzae (21), calcineurin is required for Ca 2ϩ ion homeostasis. Our laboratory previously showed that calcineurin is required for C. albicans to survive Ca 2ϩ exposure in serum and thereby for virulence (7,8). These observations suggest a general role for calcineurin in controlling Ca 2ϩ homeostasis.…”

Eca1, a Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase, Is Involved in Stress Tolerance and Virulence inCryptococcus neoformans

“…Calcineurin is required for virulence in all human-pathogenic fungi in which it has been studied, but its roles in virulence differ between species. In C. albicans, calcineurin mutants grow like the wild type at 37°C but are killed by calcium in serum (4,8,9,61). In A. fumigatus, calcineurin mutants exhibit severe morphological defects (22,66).…”

Components of the Calcium-Calcineurin Signaling Pathway in Fungal Cells and Their Potential as Antifungal Targets

“…and required for virulence and stress responses in many other major fungi (18,84,90,91). Zhang et al found that calcineurin and its downstream target CRZ1 were responsible for Candida lusitaniae's pseudohyphal growth, cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance (19).…”

“…The calcium signaling transduction system includes enzymes and proteins, such as calmodulin, calcineurin, and the transcription factors encoded by CRZl/TNC1 and PRZ1, that have been shown to be nonessential for normal growth but critical in mediating cell survival in response to stress (19,84). Calcineurin-mediated resistance has been considered one of the important factors in the failure of clinical treatment of mycoses (18,19,23), and its activation is evoked by the calcium-binding protein calmodulin (73).…”

“…(82,83). A calcium cell survival (CCS) pathway may be involved in the survival of cells subjected to a variety of cellular stresses, because the activation of a variety of Ca 2ϩ channels, calmodulin, calcineurin, and other factors is necessary for the long-term survival of cells undergoing ER stress, and the genes involved in this pathway are known to be essential in many cell biological processes; these essential components of the whole pathway would likely make good targets for antifungal therapy (19,56,(84)(85)(86).…”