RESUMO
Cryptococcus neoformans is an encapsulated fungal pathogen that causes cryptococcosis, which is a major opportunistic infection in immunosuppressed individuals. Mammalian ß-galactoside-binding protein Galectin-3 (Gal-3) modulates the host innate and adaptive immunity, and plays significant roles during microbial infections including some fungal diseases. Here we show that this protein plays a role also in C. neoformans infection. We find augmented Gal-3 serum levels in human and experimental infections, as well as in spleen, lung, and brain tissues of infected mice. Gal-3-deficient mice are more susceptible to cryptococcosis than WT animals, as demonstrated by the higher fungal burden and lower animal survival. In vitro experiments show that Gal-3 inhibits fungal growth and exerts a direct lytic effect on C. neoformans extracellular vesicles (EVs). Our results indicate a direct role for Gal-3 in antifungal immunity whereby this molecule affects the outcome of C. neoformans infection by inhibiting fungal growth and reducing EV stability, which in turn could benefit the host.
Assuntos
Antifúngicos/imunologia , Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Criptococose/imunologia , Cryptococcus neoformans/efeitos dos fármacos , Galectina 3/imunologia , Galectina 3/farmacologia , Imunidade Adaptativa , Animais , Cápsulas Bacterianas/efeitos dos fármacos , Proteínas Sanguíneas , Encéfalo/imunologia , Criptococose/microbiologia , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Galectina 3/sangue , Galectina 3/genética , Galectinas , Expressão Gênica , Humanos , Pulmão/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologiaRESUMO
Cryptococcus neoformans is an environmental fungus that can cause lethal meningoencephalitis in immunocompromised individuals. The mechanisms by which environmental microbes become pathogenic to mammals are still obscure, but different studies suggest that fungal virulence evolved from selection imposed by environmental predators. The soil-living Acanthamoeba castellanii is a well-known predator of C. neoformans. In this work, we evaluated the participation of C. neoformans virulence-associated structures in the interaction of fungal cells with A. castellanii. Fungal extracellular vesicles (EVs) and the polysaccharide glucuronoxylomannan (GXM) were internalized by A. castellanii with no impact on the viability of amoebal cells. EVs, but not free GXM, modulated antifungal properties of A. castellanii by inducing enhanced yeast survival. Phagocytosis of C. neoformans by amoebal cells and the pathogenic potential in a Galleria mellonella model were not affected by EVs, but previous interactions with A. castellanii rendered fungal cells more efficient in killing this invertebrate host. This observation was apparently associated with marked amoeba-induced changes in surface architecture and increased resistance to both oxygen- and nitrogen-derived molecular species. Our results indicate that multiple components with the potential to impact pathogenesis are involved in C. neoformans environmental interactions.
Assuntos
Acanthamoeba castellanii/fisiologia , Cryptococcus neoformans/fisiologia , Interações Microbianas , Animais , Sobrevivência Celular/efeitos dos fármacos , Criptococose/microbiologia , Modelos Animais de Doenças , Lepidópteros , Viabilidade Microbiana , Fagocitose/efeitos dos fármacos , Polissacarídeos/metabolismo , Vesículas Secretórias/metabolismo , Análise de Sobrevida , VirulênciaRESUMO
Enzymes play key roles in fungal pathogenesis. Manipulation of enzyme expression or activity can significantly alter the infection process, and enzyme expression profiles can be a hallmark of disease. Hence, enzymes are worthy targets for better understanding pathogenesis and identifying new options for combatting fungal infections. Advances in genomics, proteomics, transcriptomics, and mass spectrometry have enabled the identification and characterization of new fungal enzymes. This review focuses on recent developments in the virulence-associated enzymes from Cryptococcus neoformans. The enzymatic suite of C. neoformans has evolved for environmental survival, but several of these enzymes play a dual role in colonizing the mammalian host. We also discuss new therapeutic and diagnostic strategies that could be based on the underlying enzymology.