Antifungal Drug Development: Targeting the Fungal Sphingolipid Pathway

McEvoy, Kyle; Normile, Tyler G.; Poeta, Maurizio Del

doi:10.3390/jof6030142

Cited by 28 publications

(23 citation statements)

References 71 publications

(85 reference statements)

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“…During immunodeficiency, however, the fungus can disseminate to the brain to cause lethal meningoencephalitis. The mortality rate can be attributed to the aggressiveness of the fungus as well as limited antifungal treatment options available to combat cryptococcosis, resulting in high rates of antifungal resistance [reviewed in ( McEvoy et al., 2020 )] and host toxicity ( Bicanic et al., 2015 ). Despite extensive vaccine development research, no fungal vaccines are currently available for clinical use.…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Normile

Rella

Poeta

2021

Front. Cell. Infect. Microbiol.

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Cryptococcus neoformans is a fungal pathogen causing life-threatening meningoencephalitis in susceptible individuals. Fungal vaccine development has been hampered by the fact that cryptococcosis occurs during immunodeficiency. We previously reported that a C. neoformans mutant (Δsgl1) accumulating sterylglucosides (SGs) is avirulent and provides complete protection to WT challenge, even under CD4+ T cell depletion, an immunodeficient condition commonly associated with cryptococcosis. We found high levels of SGs in the lungs post-immunization with Δsgl1 that decreased upon fungal clearance. Th1 cytokines increased whereas Th2 cytokines concurrently decreased, coinciding with a large recruitment of leukocytes to the lungs. Depletion of B or CD8+ T cells did not affect either Δsgl1 clearance or protection from WT challenge. Although CD4+ T cell depletion affected clearance, mice were still protected indicating that clearance of the mutant was not necessary for host protection. Protection was lost only when both CD4+ and CD8+ T cells were depleted, highlighting a previously unexplored role of fungal-derived SGs as an immunoadjuvant for host protection against cryptococcosis.

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Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Normile

Rella

Poeta

2021

Front. Cell. Infect. Microbiol.

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“…Because fungal sphingolipids have different chemical structures from those of mammalian sphingolipids, they can be exploited as targets for the development of antifungal drugs. Therefore, several studies have focused on sphingolipid metabolism in fungal cells for the development of new antifungal agents [ 20 , 96 ]. A variety of compounds have been reported to act against the fungal sphingolipid biosynthetic pathway.…”

Section: The Role Of Sphingosine In Infectious Diseasesmentioning

confidence: 99%

“…A variety of compounds have been reported to act against the fungal sphingolipid biosynthetic pathway. Such compounds include natural and synthetic molecules, such as fumonisin B1 as an inhibitor of ceramide synthase or FTY720 (fingolimod) as a sphingosine-1-phosphate antagonist, as well as antibodies, which can attenuate fungal sphingolipids [ 20 , 96 ]. In recent years, monoclonal antibodies against fungal glucosylceramides (GlcCer) have been developed and proven to inhibit cryptococcal growth in vitro [ 97 ].…”

Section: The Role Of Sphingosine In Infectious Diseasesmentioning

confidence: 99%

The Anti-Infectious Role of Sphingosine in Microbial Diseases

Liu

Gulbins

et al. 2021

Cells

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Sphingolipids are important structural membrane components and, together with cholesterol, are often organized in lipid rafts, where they act as signaling molecules in many cellular functions. They play crucial roles in regulating pathobiological processes, such as cancer, inflammation, and infectious diseases. The bioactive metabolites ceramide, sphingosine-1-phosphate, and sphingosine have been shown to be involved in the pathogenesis of several microbes. In contrast to ceramide, which often promotes bacterial and viral infections (for instance, by mediating adhesion and internalization), sphingosine, which is released from ceramide by the activity of ceramidases, kills many bacterial, viral, and fungal pathogens. In particular, sphingosine is an important natural component of the defense against bacterial pathogens in the respiratory tract. Pathologically reduced sphingosine levels in cystic fibrosis airway epithelial cells are normalized by inhalation of sphingosine, and coating plastic implants with sphingosine prevents bacterial infections. Pretreatment of cells with exogenous sphingosine also prevents the viral spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from interacting with host cell receptors and inhibits the propagation of herpes simplex virus type 1 (HSV-1) in macrophages. Recent examinations reveal that the bactericidal effect of sphingosine might be due to bacterial membrane permeabilization and the subsequent death of the bacteria.

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“…Sphingolipids are emerging as a potential new target for the development of antifungal agents ( 39 ). Aureobasidin A (AbA), a natural compound that inhibits fungus-specific inositol phosphorylceramide (IPC) synthase, has potent antifungal activity against several Candida species, including C. parapsilosis ( 40 ).…”

Section: Introductionmentioning

confidence: 99%