Aspergillus Cyclooxygenase-Like Enzymes Are Associated with Prostaglandin Production and Virulence

Abstract

Oxylipins comprise a family of oxygenated fatty acid-derived signaling molecules that initiate critical biological activities in animals, plants, and fungi. Mammalian oxylipins, including the prostaglandins (PGs), mediate many immune and inflammation responses in animals. PG production by pathogenic microbes is theorized to play a role in pathogenesis. We have genetically characterized three Aspergillus genes, ppoA, ppoB, and ppoC, encoding fatty acid oxygenases similar in sequence to specific mammalian prostaglandin synthases, the cyclooxygenases. Enzyme-linked immunosorbent assay analysis showed that production of PG species is decreased in both Aspergillus nidulans and A. fumigatus ppo mutants, implicating Ppo activity in generating PGs. The A. fumigatus triple-ppo-silenced mutant was hypervirulent in the invasive pulmonary aspergillosis murine model system and showed increased tolerance to H 2 O 2 stress relative to that of the wild type. We propose that Ppo products, PG, and/or other oxylipins may serve as activators of mammalian immune responses contributing to enhanced resistance to opportunistic fungi and as factors that modulate fungal development contributing to resistance to host defenses.

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

“…As an example, A. nidulans and A. fumigatus have three dioxygenase-encoding genes, namely ppoA, ppoB and ppoC with high sequence similarity to mammalian cyclooxygenases [11]. Besides regulating sexual and asexual sporulation, all three ppo genes contribute to prostaglandin biosynthesis, possibly via oxygenating arachidonic acid, thereby generating the prostaglandin precursor PGH 2 [11]. …”

“…Nevertheless, the role of fungal prostaglandins in virulence is evident as, in all yet examined fungal species, their production has been associated with markedly altered immune responses [11,26]. To expand our knowledge about the role of fungal eicosanoids in pathogenesis, we examined lipid mediator production in another important human fungal pathogen, C. parapsilosis .…”

“…However, they lack COX and LOX required for their production, which suggests the presence of alternative routes for prostaglandin biosynthesis. Such routes have been identified in C. albicans ( FET3 and OLE2 mediated pathways) [9], C. neoformans ( LAC1 ) [10] and Aspergillus ( PPO gene family) species [11]. These fungal eicosanoids play a role in fungal pathogenesis, as deletion of LAC1 in C. neoformans resulted in attenuated virulence while disruption of PPO genes drastically reduced asexual spore formation in Aspergillus nidulans and leads to a hyper-virulent phenotype in A. fumigatus [11].…”

“…Such routes have been identified in C. albicans ( FET3 and OLE2 mediated pathways) [9], C. neoformans ( LAC1 ) [10] and Aspergillus ( PPO gene family) species [11]. These fungal eicosanoids play a role in fungal pathogenesis, as deletion of LAC1 in C. neoformans resulted in attenuated virulence while disruption of PPO genes drastically reduced asexual spore formation in Aspergillus nidulans and leads to a hyper-virulent phenotype in A. fumigatus [11]. Additionally, the yeast to hyphal transition in C. albicans is regulated in part by PGE 2 and mature biofilms also produce this prostaglandin [12,13].…”

Parallels in Fungal Pathogenesis on Plant and Animal Hosts

“…Fungal strains unable to produce these molecules are hypervirulent and have increased tolerance to hydrogen peroxide stress relative to that of the wild type. This suggests that the fungal oxylipins may activate mammalian immune responses, thus contributing to enhanced resistance to fungi (82). Oxylipin-deficient mutants of Aspergillus nidulans are less able than wild-type isolates to colonize seeds (83).…”