ArticlePLoS pathogens2023
Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis.
Article in PLoS pathogens, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Cryptococcal Infection Across Disease Stages: Host-Pathogen Interactions, Tissue Niches, and Translational Priorities.Pathogens (Basel, Switzerland) · 2026Review
- Article
- Engineering Yeast Extracellular Vesicle Biogenesis Through Rewiring Membrane Trafficking Pathways.Microbial biotechnology · 2026Article
- Review
- Dormant yet dangerous: the role of cell rest in perseverance.Future microbiology · 2025Review
- Pathogenicity and virulence of Cryptococcus neoformans from an environmental perspective.Virulence · 2025Review
- Genome restructuring and lineage diversification of Cryptococcus neoformans during chronic infection of human hosts.Cell reports · 2025Article
- Exopolysaccharides of Ganoderma lucidum Activate the NLRP3 Inflammasome, Modulating Phagocytes and the Response of Mice to Infection with Cryptococcus neoformans.Mycopathologia · 2025Article
- Immunometabolic reprogramming in macrophages infected with active and dormantInfection and immunity · 2025Article
- Research progress on immunometabolism and gut microbiota in cryptococcal meningitis: mechanisms and therapeutic implications.Frontiers in neuroscience · 2025Review
- Population heterogeneity in Cryptococcus neoformans: Impact on pathogenesis.PLoS pathogens · 2024Review
- The microbial damage and host response framework: lesson learned from pathogenic survival trajectories and immunoinflammatory responses ofFrontiers in immunology · 2024Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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