Hypoxia: A Double-Edged Sword During Fungal Pathogenesis?

Chung, Hyun‐Jung; Lee, Yong-Hwan

doi:10.3389/fmicb.2020.01920

Cited by 38 publications

(34 citation statements)

References 96 publications

(283 reference statements)

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“…The effect of hypoxic conditions on antifungal efficiency, drug resistance and diagnostic efficacy has also been investigated [ 48 , 73 , 74 , 75 ]. As such, the potential role of hypoxia in aspergillosis has been discussed in detail throughout multiple reviews [ 53 , 76 , 77 , 78 , 79 ]. Along with the many studies exploring the role of hypoxia in A. fumigatus biology and disease, a recent notable study by Gresnigt et al (2016) leveraged fluorescence tomography to investigate the interplay between inflammation, hypoxia and fungal growth in murine models of IPA [ 16 ].…”

Section: What Microenvironments Does a Fumigatus E...mentioning

confidence: 99%

Novel Insights into Aspergillus fumigatus Pathogenesis and Host Response from State-of-the-Art Imaging of Host–Pathogen Interactions during Infection

Ortiz

Pennington

Thomson

et al. 2022

JoF

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Aspergillus fumigatus spores initiate more than 3,000,000 chronic and 300,000 invasive diseases annually, worldwide. Depending on the immune status of the host, inhalation of these spores can lead to a broad spectrum of disease, including invasive aspergillosis, which carries a 50% mortality rate overall; however, this mortality rate increases substantially if the infection is caused by azole-resistant strains or diagnosis is delayed or missed. Increasing resistance to existing antifungal treatments is becoming a major concern; for example, resistance to azoles (the first-line available oral drug against Aspergillus species) has risen by 40% since 2006. Despite high morbidity and mortality, the lack of an in-depth understanding of A. fumigatus pathogenesis and host response has hampered the development of novel therapeutic strategies for the clinical management of fungal infections. Recent advances in sample preparation, infection models and imaging techniques applied in vivo have addressed important gaps in fungal research, whilst questioning existing paradigms. This review highlights the successes and further potential of these recent technologies in understanding the host–pathogen interactions that lead to aspergillosis.

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Section: What Microenvironments Does a Fumigatus E...mentioning

confidence: 99%

Novel Insights into Aspergillus fumigatus Pathogenesis and Host Response from State-of-the-Art Imaging of Host–Pathogen Interactions during Infection

Ortiz

Pennington

Thomson

et al. 2022

JoF

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“…Both C. albicans and S. aureus biofilm growth provide a localized hypoxic environment within the deepest sections of the biofilm ( 85 , 86 ). Under hypoxic conditions, C. albicans induces transcription of genes for iron metabolism, ergosterol and heme biosynthesis, fatty acid metabolism, and cell wall biosynthesis, while reducing transcription of genes involved in mitochondrial respiration and the tricarboxylic acid cycle ( 87 ). In addition to regulating C. albicans morphogenesis, Efg1p is also a key regulator of biofilm-specific gene expression under hypoxic conditions ( 88 ).…”

Section: Albicans-s Aureus Biofilm Interactionsmentioning

confidence: 99%

Metabolic Adaptations During Staphylococcus aureus and Candida albicans Co-Infection

Eichelberger

Cassat

2021

Front. Immunol.

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Successful pathogens require metabolic flexibility to adapt to diverse host niches. The presence of co-infecting or commensal microorganisms at a given infection site can further influence the metabolic processes required for a pathogen to cause disease. The Gram-positive bacterium Staphylococcus aureus and the polymorphic fungus Candida albicans are microorganisms that asymptomatically colonize healthy individuals but can also cause superficial infections or severe invasive disease. Due to many shared host niches, S. aureus and C. albicans are frequently co-isolated from mixed fungal-bacterial infections. S. aureus and C. albicans co-infection alters microbial metabolism relative to infection with either organism alone. Metabolic changes during co-infection regulate virulence, such as enhancing toxin production in S. aureus or contributing to morphogenesis and cell wall remodeling in C. albicans. C. albicans and S. aureus also form polymicrobial biofilms, which have greater biomass and reduced susceptibility to antimicrobials relative to mono-microbial biofilms. The S. aureus and C. albicans metabolic programs induced during co-infection impact interactions with host immune cells, resulting in greater microbial survival and immune evasion. Conversely, innate immune cell sensing of S. aureus and C. albicans triggers metabolic changes in the host cells that result in an altered immune response to secondary infections. In this review article, we discuss the metabolic programs that govern host-pathogen interactions during S. aureus and C. albicans co-infection. Understanding C. albicans-S. aureus interactions may highlight more general principles of how polymicrobial interactions, particularly fungal-bacterial interactions, shape the outcome of infectious disease. We focus on how co-infection alters microbial metabolism to enhance virulence and how infection-induced changes to host cell metabolism can impact a secondary infection.

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“…delemar -dependent mechanism that promotes evasion of host defenses and persistence. Hypoxia was previously shown to enhance mucormycosis ( Chung and Lee, 2020 ) and was recently highlighted as a key factor in lethal mucormycosis in severe cases of SARS-CoV-2 patients. Hypoxia was also reported to downregulate CD206 surface expression on macrophages and dendritic cells resulting in reduced dextran internalization potential ( Raggi et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Secreted Peptides From Rhizopus arrhizus var. delemar With Immunomodulatory Effects That Enhance Fungal Pathogenesis

et al. 2022

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Secreted fungal peptides are known to influence the interactions between the pathogen and host innate immunity. The aim of this study is to screen and evaluate secreted peptides from the fungus Rhizopus arrhizus var. delemar for their immunomodulatory activity. By using mass spectrometry and immuno-informatics analysis, we identified three secreted peptides CesT (S16), Colicin (S17), and Ca2+/calmodulin-dependent protein kinase/ligand (CAMK/CAMKL; S27). Culturing peripheral blood-derived monocytic macrophages (PBMMs) in the presence of S16 or S17 caused cell clumping, while culturing them with S27 resulted in the formation of spindle-shaped cells. S27-treated PBMMs showed cell cycle arrest at G0 phase and exhibited alternatively activated macrophage phenotype with pronounced reduction in scavenger receptors CD163 and CD206. Homology prediction indicated that IL-4/IL-13 is the immunomodulatory target of S27. Confirming this prediction, S27 initiated macrophage activation through phosphorylation of STAT-6; STAT-6 inhibition reversed the activity of S27 and reduced the formation of spindle-shaped PBMMs. Lastly, S27 treatment of PBMMs was associated with altered expression of key iron regulatory genes including hepcidin, ferroportin, transferrin receptor 1, and ferritin in a pattern consistent with increased cellular iron release; a condition known to enhance Rhizopus infection. Collectively, R. arrhizus var. delemar secretes peptides with immunomodulatory activities that support fungal pathogenesis. Targeting the IL-4/IL-13R/STAT-6 axis is a potential therapeutic approach to enhance the PBMM-mediated fungal phagocytosis. This represents a potential new approach to overcome lethal mucormycosis.

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Hypoxia: A Double-Edged Sword During Fungal Pathogenesis?

Cited by 38 publications

References 96 publications

Novel Insights into Aspergillus fumigatus Pathogenesis and Host Response from State-of-the-Art Imaging of Host–Pathogen Interactions during Infection

Novel Insights into Aspergillus fumigatus Pathogenesis and Host Response from State-of-the-Art Imaging of Host–Pathogen Interactions during Infection

Metabolic Adaptations During Staphylococcus aureus and Candida albicans Co-Infection

Novel Secreted Peptides From Rhizopus arrhizus var. delemar With Immunomodulatory Effects That Enhance Fungal Pathogenesis

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