Abstract
The prevalence of fungal infections has increased in immunocompromised patients, leading to millions of deaths annually. Arachidonic acid (AA) metabolites, such as eicosanoids, play important roles in regulating innate and adaptative immune function, particularly since they can function as virulence factors enhancing fungal colonization and are produced by mammalian and lower eukaryotes, such as yeasts and other fungi (Candida albicans, Histoplasma capsulatum and Cryptococcus neoformans). C. albicans produces prostaglandins (PG), Leukotrienes (LT) and Resolvins (Rvs), whereas the first two have been well documented in Cryptococcus sp. and H. capsulatum. In this review, we cover the eicosanoids produced by the host and fungi during fungal infections. These fungal-derived PGs have immunomodulatory functions analogous to their mammalian counterparts. Prostaglandin E2 (PGE2) protects C. albicans and C. parapsilosis cells from the phagocytic and killing activity of macrophages. H. capsulatum PGs augment the fungal burden and host mortality rates in histoplasmosis. However, PGD2 potentiates the effects and production of LTB4, which is a very potent neutrophil chemoattractant that enhances host responses. Altogether, these data suggest that eicosanoids, mainly PGE2, may serve as a new potential target to combat diverse fungal infections.
Highlights
Fungal infections are a major global threat, due to their increasing prevalence in immunocompromised patients [1], the limited number of therapeutic options, their chronicity, and frequently time-consuming diagnosis [2,3]
The exact molecular mechanisms behind the Candida-derived eicosanoid production are only uncovered in the case of PGs in C. albicans and C. parapsilosis
Prostaglandin E2 (PGE2) synthesis in C. albicans is regulated by OLE2, while C. parapsilosis evolved OLE2-independent PGs production pathways
Summary
Fungal infections are a major global threat, due to their increasing prevalence in immunocompromised patients [1], the limited number of therapeutic options, their chronicity, and frequently time-consuming diagnosis [2,3]. An important feature about AA-derived eicosanoids is their short response time, as their formation does not require protein synthesis, due to the fact that the AA precursor is present in mammalian cell membranes and the converting enzymes are usually constitutively expressed These compounds can be produced by lower eukaryotes, including yeasts and other fungi, having an active role during infection and representing a potential class of virulence factors [4,13]. Depending on the following enzymatic step, PGH2 can be modified to produce different PGs (PGF2α, PGD2, and PGE2), prostacyclin (PGI2) or thromboxane A2 (TXA2) [14] They regulate numerous processes throughout the body, such as kidney function, platelet aggregation, neurotransmitter release, and modulation of inflammatory responses, where they participate, among other tasks, in thermoregulation (inducing fever) and pain [5]. Nordihydroguaiaretic acid inhibited eicosanoids production and clearly impacted growth of Cryptococcus neoformans and Candida albicans, offering a link between fungal growth and eicosanoid production [50,51,52]
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