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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.
Pathogenesis of Fungal Keratitis
Published in Mahendra Rai, Marcelo Luís Occhiutto, Mycotic Keratitis, 2019
Innate immune system has specific receptors as the first line of defence against infectious invaders that allow the immune system to recognize and initiate a normal inflammatory response to invading microorganisms (Plato et al. 2015). Once hyphae invade corneal tissue, innate immune cells like macrophages, neutrophils, and dendritic cells are recruited to mediate the host defense. The NOD-like (NLR), RIG-I-like (RLR), Toll-like (TLR), and C-type Lectin-like Receptors (CLR) are four receptor families that concur to the recognition of the fungi. Several of these Pattern Recognition Receptors (PRRs) are capable to initiate innate immunity and polarize adaptive responses on the recognition of fungal cell wall components, and other molecular structures including fungal nucleic acids (Plato et al. 2015). These receptors induce effective mechanisms of fungal clearance in normal hosts, but immunosuppression, medical interventions, or genetic predisposition may increase the susceptibility to fungal infections (Plato et al. 2015). The C-type lectin-like receptors, like Dectin-1 and Dectin-2, are the major PRR involved, and mediate secretion of chemokines (CXCL 1 and CXCL2) and proinflammatory cytokines (IL-1b and TNFα) (Plato et al. 2015). Immunopathogenesis of fungal keratitis is summarized in Fig. 9.1.
Aspergillus fumigatus
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
Bronchoalveolar macrophages sense A. fumigatus through pathogen-associated membrane patterns (PAMPs) on the conidia via their Toll-like receptors TLR2 and TLR4, followed by engulfment and phagocytosis. Inhaled conidia via galactomannan bind some soluble receptors such as pentraxin-3 and lung surfactant protein D. This enhances phagocytosis and inflammatory responses. Phagosomes containing conidia fuse with endosomes followed by activation of NADPH oxidase-dependent killing. Nonoxidative mechanisms are also essential for the digestion of phagocytosed conidia by macrophages. Swelling of the conidia inside the macrophage appears to be a prerequisite for fungal killing. Conidial swelling inside macrophages or in the bronchoalveolar space alters cell wall composition and exposes fungal β-glucan. This further triggers fungicidal responses via mammalian β-glucan receptor dectin-1. However, the killing is delayed and quite slow and a total distruction of inhaled conidia by alveolar macrophages has never been reported. A. fumigatus is often able to block phagocytosis by producing hydrophobic pigments – melanins such as conidial dihydroxynaphthalene-melanin. Melanins are expressed on the conidial surface and protect the pathogen by quenching reactive oxygen species (ROS).
Rationale utilization of phospholipid excipients: a distinctive tool for progressing state of the art in research of emerging drug carriers
Published in Journal of Liposome Research, 2023
Koilpillai Jebastin, Damodharan Narayanasamy
Dectin-1 (DEC-1) and Dectin-2 (DEC-2) are mammalian immunological receptors for oligoglucans and oligomannans, respectively. Ambati et al. (2019b) developed two types of DectiSomes based on these receptors. Amphotericin B-loaded liposomes (AmB-LLs) were first formulated. AmB-LLs are pegylated analogs of AmBisome, a popular commercial antifungal drug. DEC1-AmB-LLs and DEC2-AmB-LLs, respectively, were developed by coating the AmB-LLs with the carbohydrate recognition domains of Dectin-1 and Dectin-2. Dectin dimers are formed when two monomers of Dectin float together and bind to oligoglucans and oligomannans present in fungal pathogen cell walls, exopolysaccharide matrices, and biofilms (Goyal et al. 2018). When liposomes come into contact with fungal ligands at various locations on fungal cells, the presence of a large number of Dectin molecules ensures efficient and high avidity binding. Dectin-1 and Dectin-2 work together to recognize nearly all of the 20 phyla of evolutionarily different fungal diseases, including the five main pathogens described above. The authors predicted that DectiSomes would be good pan-antifungal medications because most antifungal drugs are hydrophobic or amphiphobic and may be efficiently integrated into a liposomal membrane to boost drug tissue penetration and prolong half-life. Dectin targeting liposomal AmB improves medication efficacy and lowers the effective dose, according to their findings in vitro and in vivo (Meagher et al. 2021).
The Role of Neutrophil Extracellular Traps in the Ocular System
Published in Current Eye Research, 2022
Yingsi Li, Luoying Xie, Wenjing Song, Meiting Huang, Yu Cheng, Shudi Chen, Yuan Gao, Xiaoming Yan
NETs were observed in 14 keratitis patients with four different fungal infections. Notably, the number of NETs in infected corneas was associated with the prognosis of fungal keratitis.44 When a higher grade of NETs was formed, patients with fungal keratitis had a better treatment response and a shorter infectious course.44 Fungal invasiveness and aggressivity were enhanced with condition exacerbation because the release of NETs was dramatically reduced by Dex.52 Some pathogens, like C. albicans hyphae, are too large to be phagocytosed. Branzk et al. found the ability of neutrophils to sense microbe size and selectively release NETs in response to large pathogens.53 The recognition of microbe polysaccharides primarily occurs via C-type lectin receptors (dectin-1 and dectin-2), which act as microbe size sensors. Dectin-2 contributes to the upregulation of the inflammatory response and enhances NET formation, and dectin-1 suppresses NET release and promotes phagocytosis.53,54 Calprotectin was the critical protein of NETs in the host defense against C. albicans in vitro and in vivo.3 Complement pathways and wound-healing responses are also involved in NET-mediated host defense and jointly monitor pathogenesis during corneal fungal infection.55,56
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.