Macrophages use a bet-hedging strategy for antimicrobial activity in phagolysosomal acidification

Dragotakes, Quigly; Stouffer, Kaitlin; Fu, Man Shun; Sella, Yehonatan; Youn, Christine; Yoon, Olivia Insun; Leon-Rodriguez, Carlos M. De; Freij, Joudeh B.; Bergman, Aviv; Casadevall, Arturo

doi:10.1172/jci133938

Cited by 34 publications

(45 citation statements)

References 62 publications

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“…Given that human infection also results in rapid fungal microevolution in this host ( 86 , 87 ), it is possible that similar mechanisms occur in vivo when this fungus comes under attack by immune cells. Indeed, macrophages appear to also use a bet-hedging strategy in phagosomal acidification to control microbes ( 88 ), and several studies have shown microevolution of Cryptococcus during mammalian infection ( 72 , 87 , 89 , 90 ). A bet-hedging strategy that generates a prodigious number of phenotypes would increase survival in the face of unknown threats and could represent a general mechanism for survival in soils.…”

Section: Discussionmentioning

confidence: 99%

Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence

Liporagi-Lopes

Júnior

et al. 2021

mBio

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Section: Discussionmentioning

confidence: 99%

Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence

Liporagi-Lopes

Júnior

et al. 2021

mBio

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“…Murine bone marrow-derived macrophages (BMDMs) stimulated with gamma interferon (IFN-γ) effectively suppressed the growth of C. neoformans , and the effect of IFN-γ was augmented by lipopolysaccharide (LPS) ( 6 ). On the other hand, C. neoformans can survive and reproduce inside macrophages via several mechanisms such as inducing macrophage lysosome damage, modulating phagosomal pH, and causing alterations in the host cell cycle ( 7 , 8 ). Consequently, macrophages can be a niche for C. neoformans to survive and spread.…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Zhang

et al. 2021

mBio

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Cryptococcus neoformans causes deadly mycosis in immunocompromised individuals. Macrophages are key cells fighting against microbes. Extracellular vesicles (EVs) are cell-to-cell communication mediators. The roles of EVs from infected host cells in the interaction with Cryptococcus remain uninvestigated. Here, EVs from viable C. neoformans-infected macrophages reduced fungal burdens but led to shorter survival of infected mice. In vitro, EVs induced naive macrophages to an inflammatory phenotype. Transcriptome analysis showed that EVs from viable C. neoformans-infected macrophages activated immune-related pathways, including p53 in naive human and murine macrophages. Conserved analysis demonstrated that basic cell biological processes, including cell cycle and division, were activated by infection-derived EVs from both murine and human infected macrophages. Combined proteomics, lipidomics, and metabolomics of EVs from infected macrophages showed regulation of pathways such as extracellular matrix (ECM) receptors and phosphatidylcholine. This form of intermacrophage communication could serve to prepare cells at more distant sites of infection to resist C. neoformans infection. IMPORTANCE Cryptococcus neoformans causes cryptococcal meningitis, which is frequent in patients with HIV/AIDS, especially in less-developed countries. The incidence of cryptococcal meningitis is close to 1 million each year globally. Macrophages are key cells that protect the body against microbes, including C. neoformans. Extracellular vesicles are a group of membrane structures that are released from cells such as macrophages that modulate cell activities via the transfer of materials such as proteins, lipids, and RNAs. In this study, we found that Cryptococcus neoformans-infected macrophages produce extracellular vesicles that enhance the inflammatory response in Cryptococcus-infected mice. These Cryptococcus neoformans-infected macrophage vesicles also showed higher fungicidal biological effects on inactivated macrophages. Using omics technology, unique protein and lipid signatures were identified in these extracellular vesicles. Transcriptome analysis showed that these vesicles activated immune-related pathways like p53 in naive macrophages. The understanding of this intermacrophage communication could provide potential targets for the design of therapeutic agents to fight this deadly mycosis.

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“…Thel umens of nascent phagosomes become progressively more acidic (reaching pH % 5), in ap rocess regulated by vacuolar (V-type) ATPase. [2] Phagosomes acquire hydrolytic proteases and other proteins needed for degradative functions by continuously fusing with endosomes and lysosomes. [3] These events must occur in an ordered sequence to ensure the pathogen is killed.…”

Section: Introductionmentioning

confidence: 99%

Real‐Time Simultaneous Imaging of Acidification and Proteolysis in Single Phagosomes Using Bifunctional Janus‐Particle Probes

Lee

Zhang

2021

Angew Chem Int Ed

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The digestion of pathogens inside phagosomes by immune cells occurs through asequence of reactions including acidification and proteolysis,b ut howt he reactions are orchestrated in the right order is unclear due to al acko f methods to simultaneously measure more than one reaction in phagosomes.H ere we report ab ifunctional Janus-particle probe to simultaneously monitor acidification and proteolysis in single phagosomes in live cells.Eachprobe consists of apH reporter and aproteolysis reporter that are spatially separated but function concurrently.U sing the Janus probes,w ef ound the acidic pH needed to initiate and maintain proteolysis, revealing the mechanism for the sequential occurrence of both reactions during pathogen digestion. We showed howb acterium-derived lipopolysaccharides alter the acidification and proteolysis in phagosomes.T his study showcases Janusparticle probes as ag enerally applicable tool for monitoring multiple reactions in intracellular vesicles.

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Macrophages use a bet-hedging strategy for antimicrobial activity in phagolysosomal acidification

Cited by 34 publications

References 62 publications

Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence

Amoeba Predation of Cryptococcus neoformans Results in Pleiotropic Changes to Traits Associated with Virulence

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

Real‐Time Simultaneous Imaging of Acidification and Proteolysis in Single Phagosomes Using Bifunctional Janus‐Particle Probes

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