Novel Structural Features in Candida albicans Hyphal Glucan Provide a Basis for Differential Innate Immune Recognition of Hyphae Versus Yeast

Lowman, Douglas W.; Greene, Rachel R.; Bearden, Daniel W.; Kruppa, Michael; Pottier, Max; Monteiro, Mário A.; Soldatov, D. V.; Ensley, Harry E.; Cheng, Shih-Chin; Netea, Mihai G.; Williams, David L.

doi:10.1074/jbc.m113.529131

Cited by 114 publications

(123 citation statements)

References 64 publications

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“…These polysaccharides induce protective responses during infection (61,62). Most of the biological studies on the effects of glucans have focused on ␤-1,3-glucans (28,(63)(64)(65)(66)(67). In agreement with these data, the increase of ␤-1,3-glucans in AmB-resistant strains correlates with the enhanced response of PBMCs exposed to these isolates.…”

Section: Discussionsupporting

confidence: 74%

Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host

Mesa-Arango

Rueda

Román

et al. 2016

Antimicrob Agents Chemother

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eWe have morphologically characterized Candida tropicalis isolates resistant to amphotericin B (AmB). These isolates present an enlarged cell wall compared to isolates of regular susceptibility. This correlated with higher levels of ␤-1,3-glucan in the cell wall but not with detectable changes in chitin content. In line with this, AmB-resistant strains showed reduced susceptibility to Congo red. Moreover, mitogen-activated protein kinases (MAPKs) involved in cell integrity were already activated during regular growth in these strains. Finally, we investigated the response elicited by human blood cells and found that AmB-resistant strains induced a stronger proinflammatory response than susceptible strains. In agreement, AmB-resistant strains also induced stronger melanization of Galleria mellonella larvae, indicating that the effect of alterations of the cell wall on the immune response is conserved in different types of hosts. Our results suggest that resistance to AmB is associated with pleiotropic mechanisms that might have important consequences, not only for the efficacy of the treatment but also for the immune response elicited by the host.A mphotericin B (AmB) is a widely used antifungal drug that presents strong killing activity against fungi after binding to ergosterol. Classically, it has been described that AmB induced cell death by forming pores at the level of the cell membrane (1, 2). However, recent findings suggest that AmB elicits its fungicidal effect through multiple mechanisms. In this sense, AmB induces ergosterol sequestration, which causes alterations in the cell membrane that result in killing of the cells (3, 4). In addition, AmB induces a significant accumulation of reactive oxygen species (ROS), which has been correlated with cell damage, apoptosis induction, and death (5-9).Resistance to AmB is a complex process, and multiple mechanisms have been described to be responsible for it. Lack of ergosterol at the cell membrane has been frequently correlated with reduced susceptibility to AmB (10-14). However, there are also some cases in which resistance to AmB can occur in cells with normal ergosterol content (15, 16). Aspergillus terreus, which is a mold that presents reduced susceptibility to AmB, contains similar ergosterol content to Aspergillus fumigatus, which is fully susceptible to this antifungal. In this case, increase in catalase and reduction of ROS production have been associated with increased resistance to AmB (17). Moreover, mechanisms that protect against the production of ROS also confer reduced susceptibility to AmB (6, 9). These results indicate that AmB exerts multiple responses in the cells and that resistance to this antifungal can be acquired by different mechanisms.The correlation between the cell wall and resistance to AmB has been poorly described. A relationship between resistance to AmB and changes in the cell wall has been observed in different fungi (18)(19)(20), although it is not known to what extent changes in the cell wall contribute to amphotericin B res...

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Section: Discussionsupporting

confidence: 74%

Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host

Mesa-Arango

Rueda

Román

et al. 2016

Antimicrob Agents Chemother

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“…The relevance of these findings to fungal infection was confirmed by showing that the disappearance of CHOP proteins was produced by Candida in parallel with the formation of hyphae and the attendant exposure of ␤-glucans on budding yeasts. Since it has recently been disclosed that a unique close-chain chemical structure of hyphal ␤-glucans induce a robust production of proinflammatory responses (35), it is possible that the presence of cyclical ␤-glucans might explain the different effects of yeast and hyphal Candida on nuclear CHOP. These findings might have two relevant consequences.…”

Section: Discussionmentioning

confidence: 99%

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

Rodríguez

Domingo

Alonso

et al. 2014

Journal of Biological Chemistry

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Background: Phagocytosis and Th17 immune response control fungal invasion. Results: ␤-Glucans mobilize nuclear C/EBP homologous protein (CHOP) and increase activating transcription factor 2 (ATF2) binding to the il23a promoter. Conclusion: ␤-Glucans direct proapoptotic CHOP to phagosomal vesicles and induce ATF2-dependent il23a transcription. Significance: The mechanisms underlying the unfolded protein response and the trans-activation of il23a elicited by ␤-glucans are ascertained.

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“…It is not surprising that changes in the cell wall organization also influence the interaction of C. albicans with immune effector mechanisms. Cell wall components are major microbe-associated molecular patterns (MAMPs), which are recognized by a range of pattern recognition receptors (PRRs) on host cells triggering antimicrobial mechanisms and the release of cytokines/chemokines that modulate the resulting immune response Lowman et al, 2014;Netea et al, 2006). Alteration of the cell wall architecture will therefore ultimately lead to altered recognition responses, and indeed it has been shown that, for example, the growth of C. albicans on lactate stimulates the production of an anti-inflammatory IL-10 rather than proinflammatory IL-17 response by human peripheral blood mononuclear cells (PBMCs) (Ene, Cheng, Netea, & Brown, 2013).…”

Section: Metabolic Adaptationdnutrient and Micronutrient Acquisition mentioning

confidence: 99%

Candida Survival Strategies

Polke

Hube

Jacobsen

2015

Advances in Applied Microbiology

149

101

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Novel Structural Features in Candida albicans Hyphal Glucan Provide a Basis for Differential Innate Immune Recognition of Hyphae Versus Yeast

Cited by 114 publications

References 64 publications

Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host

Cell Wall Changes in Amphotericin B-Resistant Strains from Candida tropicalis and Relationship with the Immune Responses Elicited by the Host

The Unfolded Protein Response and the Phosphorylations of Activating Transcription Factor 2 in the trans-Activation of il23a Promoter Produced by β-Glucans

Candida Survival Strategies

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