Recognition of microbe-associated molecular patterns by pattern recognition receptors
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in 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.
Aspergillus fumigatus
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward in Case Studies in Infectious Disease, 2010
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).
Pathogenesis of Fungal Keratitis
Mahendra Rai, Marcelo Luís Occhiutto in 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.
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.
Drug delivery to macrophages: a review of nano-therapeutics targeted approach for inflammatory disorders and cancer
Published in Expert Opinion on Drug Delivery, 2020
Mahwash Mukhtar, Hussain Ali, Naveed Ahmed, Rashid Munir, Sumbal Talib, Anam S. Khan, Rita Ambrus
Glucan receptor, Dectin-1 is a pattern recognition receptor expressed by the myeloid cells including macrophages. β-glucan is the pathogen-associated molecular pattern (PAMP) for Dectin-1. This glucan is found in fungal cell walls, hence enabling Dectin-1 to identify the fungus with precision. The high specificity also enables it to recognize only 1,3-linked and 1,6-linked glucans and not the rest of glucans with other linkages [19], and hence carbohydrate with special configurations can be used as the delivery carriers. This particular receptor is also involved in endocytosis of the attached moiety and this endocytosis may serve as a potential uptake mechanism for targeted delivery vehicles [20]. β-Glucan receptors on macrophages help in the recognition of pathogenic fungi and produce an effective immune response. Studies showed the uptake of Saccharomycetes cerevisiae by dectin-1 β-Glucan receptors and ligands of these receptors showed inhibition of Candida albicans yeasts by the murine macrophages (J774 cells) [18].
Role of EphA2 in host defense against oro-pharyngeal candidiasis
Published in Journal of Oral Microbiology, 2020
The binding to EphA2 activated signal transducer activator of transcription 3 (STAT3), mitogen-activated kinase regulated kinase 1/2 and p38 signaling in an inoculum-dependent manner [23]. These actions secured the initiation of a pro-inflammatory and antifungal response. Sustained intracellular signaling by EphA2 required interaction with live yeast cells. In epithelial cells exposed to C. albicans also nuclear factor-kappa B (NF-κB) was activated. However, this was also achieved by dectin-1 in response to proliferating Candida. Dectin-1 was originally thought to function primarily on myeloid cells [28] and is a major receptor in antifungal immunity. The outgrowth of yeasts in the oral cavity caused strong receptor activation and downstream signaling through signal inducer and STAT3, as well as mitogen-activated protein kinases (MAPKs) that activate a distinct profile of chemokines, cytokines and host defense peptides [16]. Thus, activation of STAT3 stimulated expression of inflammatory molecules such as CCL20, CCL13 and S100A8 and secretion of human β-defensin 2. Also, IL-α, IL-1β and IL-8 were expressed, but independent of STAT3. This was supported by findings from EphA2 knockout mice with acute oro-pharyngeal candidiasis, which had a reduced antifungal cytokine and chemokine response in the tongue leading to a higher fungal burden and more severe disease [23].
Related Knowledge Centers
- B Cell
- Protein
- Dendritic Cell
- Monocyte
- Macrophage
- Gene
- Immunoreceptor Tyrosine-Based Activation Motif
- Glucan
- Beta-Glucan
- N-Linked Glycosylation