Inhibition of Filamentation Can Be Used To Treat Disseminated Candidiasis

Abstract

Candida albicans remains the leading causative agent of invasive fungal infection. Although the importance of filamentation in C. albicans pathogenesis has been extensively investigated, in vivo studies to date have been unable to dissect the role of this developmental process in the establishment of infection versus the development of active disease as characterized by damage to the host leading to mortality. To address this issue, we genetically engineered a C. albicans tet-NRG1 strain in which filamentation and virulence can be modulated both in vitro and in vivo simply by the presence or absence of doxycycline (DOX): this strain enabled us, in a prior study, to demonstrate that yeast-form cells were able to infect the deep organs but caused no disease unless filamentation (induced by the addition of DOX) was allowed to occur. In the present study, we examined whether inhibiting filamentation (by withdrawing the DOX) at 24 or 48 h postinfection could serve as an effective therapeutic intervention against candidiasis. The results obtained indicate that DOX removal led to an alteration in the morphology of the infecting fungal cells and a dramatic increase in survival, but as with conventional antifungal drug therapy regimens, mortality rates increased markedly the longer this intervention was delayed. These observations reinforce the importance of invasive filamentous growth in causing the damage to the host and the lethality associated with active disease and suggest this process could be fruitfully targeted for the development of new antifungal agents.Candida albicans, the main causative agent of invasive candidiasis, has become increasingly important in an expanding population of immunocompromised patients, with high morbidity and mortality rates and significant economic sequelae (1, 14-16). Management of these types of infections is complicated by the limited arsenal of antifungal drugs and the emergence of resistance to the existing classes of antifungal agents (10). Thus, there is a critical need for the development of new therapeutic approaches to combat invasive fungal infections.The role of morphogenetic changes in fungal physiology and pathogenesis has long been an active area of research, particularly in C. albicans. This opportunistic fungus grows as ovoid yeast-form cells under many laboratory conditions but transitions to a filamentous form of growth upon exposure to a mammalian host or host-like conditions (e.g., neutral pH or at 37°C in the presence of serum). The role of morphology in C. albicans pathogenesis has been explored using a number of defined mutants defective in this process and which therefore remain locked in either the nonfilamentous (yeast) or filamentous forms of growth. In general, mutants that are locked in either the yeast or filamentous forms are significantly reduced in virulence (2,3,5,6,9,12).Here, we utilize an engineered C. albicans strain that is able to filament and cause mortality when mice are fed doxycycline (DOX), yet remains nonfilamentous in the absence of DOX ...

Identification of inhibitors of yeast-to-hyphae transition in Candida albicans by a reporter screening assay

“…The morphological switch between yeast and hyphae is considered one of the most important virulence traits of C. albicans (Calderone and Fonzi, 2001), and disabling this switch abolished virulence in infection models (Saville et al, 2006). A number of chemically unrelated compounds are already known to inhibit the yeast-to-hyphae transition of C. albicans and the first applications of these compounds to infection models have been published, showing protective effects in models of mucosal infections (Akerey et al, 2009;Hisajima et al, 2008;Shareck and Belhumeur, 2011).…”

Effect of incorporation of surface pre-reacted glass ionomer filler in tissue conditioner on the inhibition of <i>Candida albicans</i> adhesion

“…A study has shown that C. albicans maintains the yeast form in normal environment and transits to the hyphal form in inflammatory environment 27) . The hyphal form has higher pathogenic potential, as it can penetrate the surface of and invade epithelial tissue 28) . Another study has reported that inhibition of the transition from the yeast to hyphal form reduces biofilm formation 29) .…”

Chemical composition and antifungal activity of the essential oils of Lavandula viridis L'Hér.

“…This finding is particularly relevant considering the fact that filamentation has long been shown to be essential for virulence in Candida albicans (Mitchell, 1998). In fact, inhibition of the dimorphic transition alone has been suggested to be sufficient to treat disseminated candidosis, thus proving to be a good target mechanism in the development of novel antifungal agents (Saville et al, 2006). Additionally, flow cytometry analyses after FUN-1 staining have revealed a dose-dependent inhibition of cell metabolism after short incubation periods with the oil at concentrations starting from the respective MIC (Fig.…”