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Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis.
de Castro, Raffael Júnio Araújo; Marina, Clara Luna; Sturny-Leclère, Aude; Hoffmann, Christian; Bürgel, Pedro Henrique; Wong, Sarah Sze Wah; Aimanianda, Vishukumar; Varet, Hugo; Agrawal, Ruchi; Bocca, Anamélia Lorenzetti; Alanio, Alexandre.
Afiliação
  • de Castro RJA; Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France.
  • Marina CL; Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil.
  • Sturny-Leclère A; Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil.
  • Hoffmann C; Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France.
  • Bürgel PH; Food Research Center, Department of Food Sciences and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
  • Wong SSW; Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil.
  • Aimanianda V; Immunobiology of Aspergillus, Institut Pasteur, Université Paris Cité, Paris, France.
  • Varet H; Immunobiology of Aspergillus, Institut Pasteur, Université Paris Cité, Paris, France.
  • Agrawal R; Plate-forme Technologique Biomics, Institut Pasteur, Université Paris Cité, Paris, France.
  • Bocca AL; Translational Mycology Research Group, National Reference Center for Invasive Mycoses and Antifungals, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France.
  • Alanio A; Laboratory of Applied Immunology, Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasília, Distrito Federal, Brazil.
PLoS Pathog ; 19(11): e1011841, 2023 Nov.
Article em En | MEDLINE | ID: mdl-38033163
ABSTRACT
Macrophages play a key role in disseminated cryptococcosis, a deadly fungal disease caused by Cryptococcus neoformans. This opportunistic infection can arise following the reactivation of a poorly characterized latent infection attributed to dormant C. neoformans. Here, we investigated the mechanisms underlying reactivation of dormant C. neoformans using an in vitro co-culture model of viable but non-culturable (VBNC; equivalent of dormant) yeast cells with bone marrow-derived murine macrophages (BMDMs). Comparative transcriptome analysis of BMDMs incubated with log, stationary phase or VBNC cells of C. neoformans showed that VBNC cells elicited a reduced transcriptional modification of the macrophage but retaining the ability to regulate genes important for immune response, such as NLRP3 inflammasome-related genes. We further confirmed the maintenance of the low immunostimulatory capacity of VBNC cells using multiplex cytokine profiling, and analysis of cell wall composition and dectin-1 ligands exposure. In addition, we evaluated the effects of classic (M1) or alternative (M2) macrophage polarization on VBNC cells. We observed that intracellular residence sustained dormancy, regardless of the polarization state of macrophages and despite indirect detection of pantothenic acid (or its derivatives), a known reactivator for VBNC cells, in the C. neoformans-containing phagolysosome. Notably, M0 and M2, but not M1 macrophages, induced extracellular reactivation of VBNC cells by the secretion of extracellular vesicles and non-lytic exocytosis. Our results indicate that VBNC cells retain the low immunostimulatory profile required for persistence of C. neoformans in the host. We also describe a pro-pathogen role of macrophage-derived extracellular vesicles in C. neoformans infection and reinforce the impact of non-lytic exocytosis and the macrophage profile on the pathophysiology of cryptococcosis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Criptococose / Cryptococcus neoformans / Vesículas Extracelulares Limite: Animals Idioma: En Revista: PLoS Pathog Ano de publicação: 2023 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Criptococose / Cryptococcus neoformans / Vesículas Extracelulares Limite: Animals Idioma: En Revista: PLoS Pathog Ano de publicação: 2023 Tipo de documento: Article País de afiliação: França