Abstract
Macrophages are key players during Paracoccidioides brasiliensis infection. However, the relative contribution of the fungal response to counteracting macrophage activity remains poorly understood. In this work, we evaluated the P. brasiliensis proteomic response to macrophage internalization. A total of 308 differentially expressed proteins were detected in P. brasiliensis during infection. The positively regulated proteins included those involved in alternative carbon metabolism, such as enzymes involved in gluconeogenesis, beta-oxidation of fatty acids and amino acids catabolism. The down-regulated proteins during P. brasiliensis internalization in macrophages included those related to glycolysis and protein synthesis. Proteins involved in the oxidative stress response in P. brasiliensis yeast cells were also up-regulated during macrophage infection, including superoxide dismutases (SOD), thioredoxins (THX) and cytochrome c peroxidase (CCP). Antisense knockdown mutants evaluated the importance of CCP during macrophage infection. The results suggested that CCP is involved in a complex system of protection against oxidative stress and that gene silencing of this component of the antioxidant system diminished the survival of P. brasiliensis in macrophages and in a murine model of infection.
Highlights
Paracoccidioidomycosis (PCM) is a human systemic mycosis that is restricted to Latin America, Brazil, Colombia and Venezuela [1]
The results suggested that cytochrome c peroxidase (CCP) is involved in a complex system of protection against oxidative stress and that gene silencing of this component of the antioxidant system diminished the survival of P. brasiliensis in macrophages and in a murine model of infection
The metabolic changes detected in P. brasiliensis reflect how the yeast cells sense the hostile environment in macrophages
Summary
Paracoccidioidomycosis (PCM) is a human systemic mycosis that is restricted to Latin America, Brazil, Colombia and Venezuela [1]. The disease is caused by members of the Paracoccidioides genus. These fungi are thermo-dimorphic species that grow as mycelium under saprobic conditions at 22–26°C, or as pathogenic yeast at 36°C [2]. The fungus converts to the yeast pathogenic form at body temperature [4]. Macrophages constitute one of the primary defense mechanisms against infection by P. brasiliensis; PCM is considered to be a classic granulomatous disease [5,6]. As a facultative intracellular pathogen, P. brasiliensis can persist inside macrophages. Microscopic studies showed that P. brasiliensis multiplied intracellularly in macrophages and this could be a factor in pathogenicity [5,6,7,8]
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