Lactate signalling regulates fungal β-glucan masking and immune evasion

Ballou, Elizabeth R.; Avelar, Gabriela Mól; Childers, Delma S.; Mackie, Joanna; Bain, Judith M.; Wagener, Jeanette; Kastora, Stavroula; Panea, Mirela D; Hardison, Sarah E.; Walker, Louise A.; Erwig, Lars P.; Munro, Carol A.; Gow, Neil A. R.; Brown, Gordon D.; MacCallum, Donna M.; Brown, Alistair J. P.

doi:10.1038/nmicrobiol.2016.238

Cited by 226 publications

(383 citation statements)

References 51 publications

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“…The settings mimicked different degrees of oxidative (0.25, 0.5, 1, and 5 mM hydrogen oxide (H 2 O 2 )), Nitrosative (1, 5, and 20 mM sodium nitrite (NaNO 2 ) (Fisher scientific)), cell wall (0.005, 0.01, 0.05% sodium dodecyl sulphate (SDS) (Fisher scientific)), osmotic (0.05, 0.1, 0.3 M sodium chloride (NaCl)) (Sigma-Aldrich) and antifungal pressure (0.5, 1, 2.5, 5 µg / mL Amphotericin B (AmB) (Sigma Aldrich) stress. The spores were counted and adjusted to 10 5 cells /mL in sf DMEM containing the stress factor at the respective concentrations in a 48 well plate, and incubated at 37° C and 5% CO 2 for 24 h. To evaluate the influence of the stress factor on the spores, serial dilutions were plated and colony forming units (CFUs) counted after 24 h (parent) or 48 h (cured) spores.…”

Section: Methodsmentioning

confidence: 99%

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Itabangi

Pcs

Zhou

et al. 2019

Preprint

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Environmentally ubiquitous fungal spores of the Mucorales order cause acute invasive infections through germination and evasion of the mammalian host immune system. Early phagocyte control of spore germination plays a key role in controlling infection, yet swelling Mucorales spores evade phagocytosis through an unknown mechanism. Here we investigate fungal immune evasion in a clinical isolate of Rhizopus microsporus and reveal the role of a bacterial endosymbiont, Ralsonia pickettii, in fungal pathogenesis. Analysis of phagocytosis rates in wild type and cured fungal isolates demonstrates a role for the endosymbiont in immune cell evasion through disruption of the cytoskeleton and phagosome maturation. Further analysis of bacterial secreted products revealed the presence of a previously uncharacterized secondary metabolite whose production is induced by the presence of the fungus. Analysis of the bacterial genome and condition-dependent RNAseq implicate a cryptic type I polyketide synthase. Subsequent analysis of wild type and cured spores in a zebrafish larvae model of infection demonstrate a role for the endosymbiont in suppressing macrophage and neutrophil recruitment to the site of infection. Finally, we demonstrate that this has implications for fungal clearance in an immunocompetent murine model of infection. Together, these findings identify for the first time a role for a bacterial endosymbiont in the pathogenesis of Rhizopus microsporus during animal infection.

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Section: Methodsmentioning

confidence: 99%

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Itabangi

Pcs

Zhou

et al. 2019

Preprint

Self Cite

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“…Due to the abundant amount of mannan on the cell wall, β-glucan exhibits a very limited, punctate pattern of nanoscale surface exposure. The extent of this glucan masking is influenced by environmental conditions such as intestinal pH or lactate levels [10, 11]. In addition, interactions with neutrophils have been shown to “unmask” the mannose layer through a neutrophil extracellular trap-mediated mechanism [12].…”

Section: Introductionmentioning

confidence: 99%

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Anaya

Wester

et al. 2019

Preprint

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Candidemia is the most common bloodstream infection in the United States. During 23 infection, the fungal cell wall is an important virulence factor, playing roles in adhesion, 24 immune recognition and colonization. The human innate immune system recognizes β-25 glucan, a highly immunogenic component of the fungal cell wall. During innate immune 26 recognition of Candida, the organization of cell wall β-glucan is an important 27 determinant of a successful immune activation. However, there have been many reports 28 showing conflicting biological activities of β-glucans with different size, branching and 29 structure. Here, using quantitative fluorescence imaging techniques, we investigate how 30 differential size and structure of β-glucan impacts activation of the innate immune 31 receptor, Dectin-1A. Our results indicate a positive correlation between highly structured 32 glucans and Dectin-1A activation. Furthermore, we determined this is due to the higher 33 ordered β-glucan causing Dectin-1A receptors to form aggregates that are below 15 nm 34 in size. Finally, Dectin-1A receptor aggregation has also been shown to form at fungal 35 particle contact sites with high β-glucan exposure. 36 Abstract 37Dectin-1A is a C-type Lectin innate immunoreceptor that recognizes β-(1,3:1,6)-glucan, 38 a structural component of Candida species cell walls. The higher order structure of β-39 glucans ranges from random coil to insoluble fiber due to varying degrees of tertiary 40 (helical) and quaternary structure. Model Saccharomyces cerevisiae β-glucans of 41 medium and high molecular weight (MMW and HMW, respectively) are highly 42 structured. In contrast, low MW glucan (LMW) is much less structured. Despite similar 43 affinity for Dectin-1A, the ability of glucans to induce Dectin-1A mediated calcium influx 3 44and Syk phosphorylation positively correlates with their degree of higher order structure. 45Chemical denaturation and renaturation of MMW glucan showed that glucan structure 46 determines agonistic potential, but not binding affinity, for Dectin-1A. We explored the 47 6 113 ITAM domains poorly recruit and activate Syk for downstream signaling [44], suggesting 114 that hemITAM domains with their single phosphotyrosine site would be poorly activating 115 in a monomeric configuration. Consistent with this hypothesis, another (hem)ITAM 116 bearing receptor, CLEC-2, is reported to require dimerization for its signaling [45]. By 117 analogy to this and other (hem)ITAM receptors, it is hypothesized that Dectin-1A must 118 oligomerize to recapitulate a multivalent binding site for Syk and to facilitate signal 119 transduction [8,45,46]. However, this prediction has not been directly explored for 120Dectin-1A in live cells at the molecular level with relation to structural determinants of 121 receptor-ligand complex organization and signaling outcomes. 122In this study, we propose that factors that induce an aggregated membrane organization 123 of Dectin-1A during activation are very important for determining signaling ...

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“…This is most clearly seen during infection of macrophages by C. albicans in vitro, where the initial repression of fungal glycolysis is reversed coinciding with C. albicans egressing from macrophages and finding glucose again [44,93]. Again, utilisation of lactate might serve a few different functions for C. albicans, enabling the fungus not only to proliferate, but also to evade immunity by impacting on cell surface structure and immune cell interactions [104]. Whether these mechanisms of macrophage escape through hyphal formation and dynamic reprogramming of fungal metabolism also operate in vivo remains to be understood.…”

Section: Candida Albicansmentioning

confidence: 99%

“…Finally, lactate is thought to be an important carbon source for C. albicans in humans, where it is produced by other microbiota and by activated inflammatory phagocytes that have switched to Warburg metabolism. Again, utilisation of lactate might serve a few different functions for C. albicans, enabling the fungus not only to proliferate, but also to evade immunity by impacting on cell surface structure and immune cell interactions [104].…”

Section: Candida Albicansmentioning

confidence: 99%

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

Traven

Naderer

2019

EMBO Reports

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Antimicrobial drug resistance is threatening to take us to the “pre‐antibiotic era”, where people are dying from preventable and treatable diseases and the risk of hospital‐associated infections compromises the success of surgery and cancer treatments. Development of new antibiotics is slow, and alternative approaches to control infections have emerged based on insights into metabolic pathways in host–microbe interactions. Central carbon metabolism of immune cells is pivotal in mounting an effective response to invading pathogens, not only to meet energy requirements, but to directly activate antimicrobial responses. Microbes are not passive players here—they remodel their metabolism to survive and grow in host environments. Sometimes, microbes might even benefit from the metabolic reprogramming of immune cells, and pathogens such as Candida albicans, Salmonella Typhimurium and Staphylococcus aureus can compete with activated host cells for sugars that are needed for essential metabolic pathways linked to inflammatory processes. Here, we discuss how metabolic interactions between innate immune cells and microbes determine their survival during infection, and ways in which metabolism could be manipulated as a therapeutic strategy.

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Lactate signalling regulates fungal β-glucan masking and immune evasion

Cited by 226 publications

References 51 publications

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

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