Lipid mediators, derived from arachidonic acid metabolism, play an important role in immune regulation. The functions of bioactive eicosanoids range from modulating cytokine signaling and inflammasome formation to anti-inflammatory and pro-resolving activities. Human pathogenic fungi such as Candida albicans, Candida parapsilosis, Cryptococcus neoformans and Aspergillus fumigatus have been shown to produce such lipid mediators, associated with their virulence. To date, investigations into the molecular mechanisms of fungal eicosanoid biosynthesis in different species have revealed that several genes are associated with prostaglandin production. However, these routes remain uncharacterized in C. parapsilosis with early results suggesting it uses pathways distinct from those found in C. albicans. Therefore, we aimed to identify and characterize C. parapsilosis genes involved in eicosanoid biosynthesis. Following arachidonic acid treatment of C. parapsilosis cells, we identified several genes interfering with prostaglandin production. Out of the identified genes, homologues of a multi copper oxidase (FET3), an Acyl-CoA thiolase (POT1) and an Acyl-CoA oxidase (POX1-3) were found to play a significant role in prostaglandin synthesis. Furthermore, all three genes were confirmed to enhance C. parapsilosis pathogenicity, as the corresponding deletion mutants were cleared more efficiently by human macrophages and induced higher levels of pro-inflammatory cytokines. In addition, the mutants were less virulent than the wild-type strain in a mouse model of systemic infection. Taken together, we identified three genes that regulate eicosanoid biosynthesis in C. parapsilosis and impact the fungus' virulence.

TC was supported the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreements FP7-PEOPLE-2013-ITN-606786 ‘ImResFun’ and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No H2020-MSCAITN-2014-642095. AG was funded by NKFIH NN 113153, by GINOP-2.3.2-15-2016-00035, by GINOP-2.3.3-15-2016-00006 and by OTKA-NKFIH K123952. RT was supported by TÁMOP 4.2.4. A/2-11-1-2012-0001 National Excellence Program - Elaborating and operating an inland student and researcher personal support system convergence program. MH and MG lab was supported by the Leiden University Medical Centre, Leiden, The Netherlands. ET was supported the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreements FP7-PEOPLE-2013-ITN-606786 ‘ImResFun’ and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No H2020-MSCAITN-2014-642095. TG group acknowledges support of the Spanish Ministry of Economy and Competitiveness grants, ‘Centro de Excelencia Severo Ochoa 2013-2017ʹ SEV-2012-0208, and BFU2015-67107 cofounded by European Regional Development Fund (ERDF); from the CERCA Programme/Generalitat de Catalunya; from the European Union and ERC Seventh Framework Programme (FP7/2007-2013) under grant agreement FP7-PEOPLE-2013-ITN-606786, and a grant from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No H2020-MSCA-ITN-2014-642095.