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Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Among the most studied CLRs are Dectin-1 (Group V, Ca++-independent) and Dectin-2 (Group II, Ca++-dependent). Dectin-1 plays a key role in antifungal immunity by initiating signals that lead to phagocytosis and killing of fungi. Expressed on macrophages, monocytes, DCs, neutrophils, microglia, and eosinophils, Dectin-1 binds β-glycans, a major cell-wall component of nearly all fungi. Deficiencies in Dectin-1 or CARD9 in mice and humans result in increased susceptibility to fungal infections. In mice, for example, Dectin-1 deficiency causes increased mortality in response to infection by fungal pathogens such as Candida albicans, Aspergillus fumigatus, and Coccoidiodes podasii. Some patients with familial chronic mucocutaneous candidiasis have a nonsense mutation in the Dectin-1 gene. Dectin-1 also appears to contribute to mucosal myeloid cell sensing of enteric commensal fungi, thereby contributing to the maintenance of “mucosal homeostasis.” For example, mice with Dectin-1 deficiency (Clec7a-/-) show an increased mucosal inflammatory response to commensal fungi in dextran sodium sulfate-induced colitis. Further, a single nucleotide polymorphism in the human Dectin-1 CLEC7A gene in patients with ulcerative colitis is associated with medically refractory disease.
The immune response to fungal challenge
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Jeffery Hu, Jeffery J. Auletta
Additional PRRs relevant to fungal pathogens include C-type lectin receptors (CLR) [20], including β-glucan (Dectin-1) [21,22] and mannose receptors (MRs) [23], and complement receptors (CRs). Like TLRs, these PRRs are located on the surface of phagocytes, including macrophages, DCs, and neutrophils, and can modulate immune cell function [24]. Dectin 1 (also known as CLEC7A) is the most well-studied CLR expressed on monocytes and macrophages. Ligation of Dectin-1 and MRs initiates phagocytosis in the absence of opsonization (see sections on phagocytosis and complement below), whereas dual ligation of complement receptors, like CR3 (CD11b/CD18 or Mac-1), with receptors for the Fc portion of immunoglobulins (FcRs) dramatically enhance microbial phagocytosis [25]. Additionally, dectin-1 is involved in inducing cytokine production and amplification of response from TLR2 or TLR4 pathway [26,27]. Dectin-1 accomplishes this task via two intracellular signaling: the spleen tyrosine kinase (SYK), caspase activation and recruitment domain containing 9 (CARD9), and protein kinase Cδ pathway [28–32] and the RAF1 kinase signaling pathway [33]. Polymorphisms in the Dectin 1 gene are associated with colonization of the genitourinary tract by Candida species, recurrent vulvovaginal candidiasis, and other fungal infection [34–37] whereas CARD9 deficiency showed more severe phenotype demonstrating increased susceptibility to invasive candidiasis [31]. While many other PRRs exist such as NOD-like receptors (NLR), the overall goal of PRRs serves to initially detect infection and coordinate the appropriate response through crosstalk and synergism between PRR and their downstream adaptor protein.
Understanding the genetic basis of immune responses to fungal infection
Published in Expert Review of Anti-infective Therapy, 2022
Samuel M. Gonçalves, Cristina Cunha, Agostinho Carvalho
Considering their central role in the regulation of antifungal immunity, the impact of genetic variation in CLRs in susceptibility to fungal infection has been widely studied. The critical role for genetic variability of dectin-1 (CLEC7A) in antifungal immunity was initially demonstrated in patients with recurrent fungal infections carrying the early stop codon polymorphism rs16910526 (Y238X) [27]. This SNP truncates dectin-1 at the carbohydrate recognition domain and leads to impaired surface expression of the receptor and defective production of cytokines by myeloid cells, particularly IL-17, in response to stimulation with Candida albicans. As a result, Y238X has been implicated in mucosal and gastrointestinal fungal colonization [28,29], but not in candidemia [30]. The non-synonymous variant rs16910527 (I223S) in dectin-1 was instead associated with lower levels of IFN-γ and an increased risk of oropharyngeal candidiasis in HIV patients [31]. This suggests that different pathogenetic variations in dectin-1 with specific structural consequences may elicit distinct susceptibility mechanisms and fungal disease entities.
Therapeutic manipulation of gut microbiota by polysaccharides of Wolfiporia cocos reveals the contribution of the gut fungi-induced PGE2 to alcoholic hepatic steatosis
Published in Gut Microbes, 2020
Shanshan Sun, Kai Wang, Li Sun, Baosong Cheng, Shanshan Qiao, Huanqin Dai, Wenyu Shi, Juncai Ma, Hongwei Liu
Fungal component and metabolite have been causatively associated with the development of AHS.10,27 Translocation of fungal β-D-glucan into circulation induced liver inflammation via the CLEC7A receptor.10 The candidalysin secreted from C. albicans promotes alcohol-associated liver disease by damaging primary hepatocytes.27 In the current study, a gut fungi-induced increase of PGE2 production in the liver was revealed as one of the mechanisms responsible for the hepatic fat accumulation and inflammatory injury in mice with chronic ethanol feeding. An increased expression of the key enzymes of PGE2 synthesis was observed in human NASH livers as compared to controls.28 The roles of PGE2 in the development of fatty liver diseases are complicated. Some evidence indicated that prostaglandins could contribute to the development of steatosis by enhancing lipid accumulation in liver and suppressing VLDL synthesis and β-oxidation.29,30 In other reports, PGE2 was demonstrated to reduce the expression of enzymes involved in de novo lipogenesis in the liver.31 As to the liver inflammatory injury, PGE2 was reported to inhibit the production of tumor necrosis factor α (TNF-α) from macrophages and Kupffer cells via EP2 and EP4 receptors, and thus attenuating the hepatic inflammation.32,33 In this study, the increase of liver TNF-α in the mice receiving ethanol could be ascribed to the ethanol-induced LPS overproduction that overwhelmed the anti-inflammatory effect of PGE2. In addition, the endogenous PGE2 was found to induce MCP-1 expression via EP4 signaling.34,35
Identification of immune-associated prognostic biomarkers in lung adenocarcinoma on the basis of gene co-expression network
Published in Immunopharmacology and Immunotoxicology, 2023
Jianhai Zhang, Ange Chen, Zhang Xue, Chengzhi Liang
Low expression of protective factors such as Endosome-Lysosome Associated Apoptosis And Autophagy Regulator 1 (KIAA1324), CKLF Like MARVEL Transmembrane Domain Containing 7 (CMTM7), C-Type Lectin Domain Containing 7 A (CLEC7A) and B-Cell Antigen Receptor Complex-Associated Protein Alpha Chain (CD79A) in the prognostic model was associated with poor prognoses of LUAD patients. Studies have found that KIAA1324 is a prognostic protective factor for gastric cancer. Kang et al. [34] revealed that KIAA1324 expression is remarkably inhibited in gastric cancer tissues, and cell experiments demonstrated that inducing normal expression of KIAA1324 significantly inhibits tumor weight and size. It was also revealed that KIAA1324 can hamper the development of gastric cancer through inhibiting the activity of Heat Shock Protein Family A Member 5 (GRP78) oncoprotein [34]. CD79A participates in B cell antigen receptor (BCR) signaling pathway. It forms membrane heterodimer with CD79B, initiates signal transduction cascade, and performs its function through antigen and BCR activation [35,36]. CLEC7A encodes Dectin 1, an innate immune receptor that is vital in anti-fungal immunity. Dectin 1 exerts a critical function in T cell activation and signaling pathways. Developing signaling pathways targeting Dectin 1 is a new idea for immunotherapy of pancreatic ductal adenocarcinoma. Dectin 1 also recognizes glycerol structures on tumor cells that activate NK cells to kill tumor cells [37,38]. The prognostic effect of protective factors in our prognostic model is consistent with published literature, and these protective genes have been reported to be protective factors for some cancers. Moreover, the genes we found actively participate in immune cell signaling pathways and may play a significant role in tumor therapy.