Role ofPLB1in Pulmonary Inflammation and Cryptococcal Eicosanoid Production

Abstract

Cryptococcal phospholipase (PLB1) is a secreted enzyme with lysophospholipase hydrolase and lysophospholipase transacylase activities. To investigate the role ofPLB1in the evasion of host immune responses, we characterized pulmonary immune responses to the parental (H99), theplb1mutant, and theplb1^recreconstituted mutant strains ofCryptococcus neoformansin mice.PLB1was required for virulence during infection acquired via the respiratory tract. Mice infected with either H99 or theplb1^recstrain generated a nonprotective inflammatory response with subsequent eosinophilia, while mice infected with theplb1mutant generated a protective immune response that controlled the infection. BecausePLB1is believed to facilitate virulence through host cell lysis, we examined the interaction of these strains with macrophages. Theplb1^recmutant exhibited decreased survival during coculture with macrophages. One factor which may be involved in the survival of yeast in the presence of macrophages is fungal eicosanoid production. Host eicosanoids have been shown to down-modulate macrophage functions.plb1exhibited a defect in eicosanoid production derived from exogenous arachidonoyl-phosphatidylcholine, suggesting thatPLB1is required for the release of arachidonic acid from phospholipids. These data suggest that cryptococcalPLB1may act as a virulence factor by enhancing the ability to survive macrophage antifungal defenses, possibly by facilitating fungal eicosanoid production.