Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization

Wu, Yifan; Zeng, Zhimin; Guo, Yubiao; Song, Lizhen; Huang, Xinyan; Zeng, Yuying; Bimler, Lynn; Chang, Chung‐Che; Knight, John; Valladolid, Christian; Sun, Hua; Crúz, Miguel A.; Hube, Bernhard; Naglik, Julian R.; Luong, Amber U.; Kheradmand, Farrah; Corry, David B.

doi:10.1016/j.immuni.2021.08.009

Cited by 51 publications

(50 citation statements)

References 76 publications

(76 reference statements)

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“…However, Dkk-1 is implicated in bone destructive phenotypes and osteoclast activation that characterize autoimmune joint diseases such as rheumatoid arthritis ( 53 , 54 ). As Dkk-1 plasma levels are also increased in asthma and CRS ( 15 ), the latter including clinically significant destructive changes of the bones surrounding involved sinuses ( 24 , 55 ), our findings suggest that Dkk-1 could represent a factor common in mouse and human allergic disease contexts that explains the consistent link to osteoclast differentiation. Activated platelets also display enhanced mRNA processing activity resulting in distinct mRNA isoforms (alternative splicing) ( 56 ), a molecular feature common to other activated inflammatory cells linked to unified airway disease ( 57 – 62 ).…”

Section: Discussionmentioning

confidence: 60%

“…In contrast to molds such as A. niger, C. albicans induces eosinophilic inflammation not through proteinases and fibrinogen, but rather through a distinct virulence factor, candidalysin ( 52 ), that activates platelets through the von Willebrand factor receptor GP1bα. Candidalysin-activated platelets release the Wnt-beta catenin pathway antagonist dickkopf-1 (Dkk-1) that coordinately promotes Th2 and Th17 differentiation that drives disease expression ( 15 ).…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of dupilumab in the treatment of severe allergic asthma and CRS and studies in STAT6-deficient mice highlight the central role of the IL4/IL13-IL4Ra-STAT6 signaling pathway in developing eosinophilic asthma (8)(9)(10). Additionally, our group has pioneered the emerging paradigm that fungi are fundamental causes of both asthma and CRS (4,5,11) through the elaboration of key virulence factors such as proteinases (12), cytokines [cleaved fibrinogen (13,14)], and candidalysin (15). Using an A. niger challenge-based mouse model of allergic asthma, STAT6-deficient mice failed to develop airway hyperresponsiveness and pulmonary eosinophilia (16).…”

Section: Introductionmentioning

confidence: 99%

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STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

et al. 2022

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Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger, and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing the spliceosome, osteoclast differentiation, and coagulation pathways. Utilizing a specific inhibitor and gene-deficient mice, we demonstrate that STAT6 is required for mycosis-induced sinus inflammation. These findings confirm the relevance of this new model and portend future studies that further extend our understanding of the immunopathologic basis of airway mycosis and unified airway disease.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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STAT6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis and Asthma, A Model of Unified Airway Disease

et al. 2022

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“…from the gut in high-risk patients has been shown to be preceded by alterations of the mycobiome [36] . Additionally, the C. albicans peptide toxine Candidalysin triggers a platelet-mediated Th2 and Th17 cell activation which is contributing to a protective allergic response in the lung [37] . Farnesol, a fungal quorum sensing molecule, can modulate the maturation of human dentritic cells [38] , [39] .…”

Section: The Mycobiome and Its Environmentmentioning

confidence: 99%

Analyzing the human gut mycobiome – A short guide for beginners

Thielemann

Herz

Kurzai

et al. 2022

Computational and Structural Biotechnology Journal

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The human body is a dynamic ecosystem consisting of millions of microbes which are often comprised under the term microbiome. Compared to bacteria, which count for the overwhelming majority of the microbiome, the number of human-associated fungi is small and often underestimated. Nonetheless, they can be found in different host niches such as the gut, the oral cavity and the skin. The fungal community has several potential roles in health and disease of the human host. In this review we will focus on intestinal fungi and their interaction with the host as well as bacteria. We also summarize technical challenges and possible biases researchers must be aware of when conducting mycobiome analysis.

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“…Epithelial recognition of candidalysin activity subsequently drives a number of critically important innate cellular immune responses, including the proliferation of tissue-resident interleukin-17 (IL-17)-producing CD4 + T cell receptor αβ-positive (TCRαβ + ) type 17 immune cells in murine oral tissue ( 14 ), neutrophil recruitment to the kidney ( 15 ) and brain ( 16 ) during murine systemic infection, and the secretion of IL-1β from macrophages via NLRP3 inflammasome activation ( 17 , 18 ). Candidalysin also elicits protective allergic responses via platelet-mediated T helper 2 (Th2) and Th17 cell polarization ( 19 ).…”

Section: Introductionmentioning

confidence: 99%