Bmh1p (14-3-3) mediates pathways associated with virulence in Candida albicans

Abstract

The ability of the pathogenic fungus Candida albicans to cause disease requires rapid adaptation to changes in the host environment and to an evolving host immune response. The identification of 'virulence factors' using in vitro characterization of mutant strains has traditionally relied on a common set of phenotypic and biochemical assays (most often performed at 30 6C) and the subsequent correlation with their corresponding virulence in mouse models of disease. Utilizing a panel of isogenic mutants for the multifunctional signal-modulating 14-3-3 protein (Bmh1p), we have found that specific mutations affect a variety of different pathways currently associated with virulence, including those involved with the formation of filaments, as well as interaction with host immune cells. Surprisingly, our studies revealed that deficiencies in many of these pathways do not always correlate with virulence in a mouse model of disseminated infection. Mutations within the binding pocket of Bmh1p that affect the ability of the protein to efficiently bind ligand had varying effects on the results of a number of in vitro and in vivo assays. The capability, in vitro, to filament in embedment conditions, and to filament and form chlamydospores under microaerophilic conditions on cornmeal agar, does not correlate with virulence. It is likely that only a subset of hyphal signalling pathways is actually required for the establishment of infection in the disseminated mouse model. Most importantly, our results suggest that the delayed onset of lagphase growth in vitro at 37 6C, and not at 30 6C, results in an inability of these mutants to rapidly adjust to environmental changes in vivo and may be responsible for their increased clearance and reduced virulence. It is critical, therefore, that future in vitro studies of putative virulence factors in C. albicans include careful characterization at physiological temperatures.

Unveiling equal importance of two 14‐3‐3 proteins for morphogenesis, conidiation, stress tolerance and virulence of an insect pathogen

“…More importantly, the fungal‐killing action irrespective of culticular or cuticle‐bypassing infection was delayed by ∼50% in our deletion and deletion/silence mutants, an indication of attenuated virulence as seen in the Δ Bmh1 mutant of C. albican s (Kelly et al ., ). This could be partially attributable to their slower growth and perturbed cell cycle, as clued by fewer blastospores formed in host haemolymph ∼4 days after infection.…”

14-3-3 proteins as potential therapeutic targets

“…Evidence now is emerging that demonstrates the differential expression patterns of 14-3-3 in healthy controls verses patients with aliments such as joint inflammation [54], multiple sclerosis [55–56] and endometriosis [57]. Furthermore, studies have revealed abnormalities in signaling mediated by 14-3-3 in diseases such as glaucoma [58], phospholipidosis [59] and infectious diseases [60–61]. It appears that altered interactions between 14-3-3 and client proteins may be responsible for a variety of dieases.…”

The 14-3-3 Gene Function of Cryptococcus neoformans Is Required for its Growth and Virulence

“…In Saccharomyces cerevisiae, two 14-3-3 genes, BMH1 and BMH2 [39], are required for multiple functions, including several downstream events of the RAS-mediated pathway [40], exocytosis, and vesicular transport steps [11]. In Candida albicans, its 14-3-3 protein is required for vegetative growth and optimal filamentation, suggesting its role in the regulatory pathways required for colonization and invasion [21]. As the 14-3-3 protein has multiple roles in different organisms and because of its abundance in the CnMVs, we are interested to know whether the C. neoformans 14-3-3 protein plays any pathological role during infection.…”