The Effects of Lipid Modulators During Cryptococcus Infection: from the Pathogen to the Host

Eicosanoids are lipid modulators made from the oxidation of arachidonic acid, a 20-carbon fatty acid; they are crucial participants in the regulation of the immune system by modulating the production of cytokines and infiltration of immune cells to the site of inflammation. Fungal pathogens can produce eicosanoids when arachidonic acid is present. C. neoformans genes PLBL1 and LAC1 are both involved in the biosynthesis of eicosanoids and deletion of these genes diminish the virulence of Cryptococcus. The overall goal of this dissertation is to identify genes involved in the synthesis of eicosanoids in Cryptococcus, and the effect of fungal and mammalian eicosanoids during cryptococcal infection.

With the use of RNA-seq analyses, we have identified a gene involved in the trafficking of eicosanoids in Cryptococcus and the modulation of host responses during cryptococcosis. Antifungal resistance 2 (Afr2), is an efflux pump that is associated with antifungal resistance. We found that AFR2 plays a role in the export of PGE2 and LTB4, two major eicosanoids of Cryptococcus. Furthermore, AFR2 is involved in virulence of C. neoformans.

Furthermore, we sought to determine the role of 5-lipoxygenase (5-LO) during cryptococcal infection. We determined that during pulmonary infection with C. neoformans, 5-LO deficient mice have an increase in inflammatory response while leucocyte infiltration decreased. However, there was no significant difference in overall mortality rates. Meanwhile infection with C. neoformans in 5-LO KO mice exhibited reduced pathology and decrease in myeloid cells infiltrating the brain and less production of Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) cytokines CCL2 (MCP-1) and CCL3 (MIP-1), suggesting that 5-LO could play a role in reducing pathology and mortality rates associated with Cryptococcus-associated IRIS.