The SARS-CoV-2 virion has shown remarkable resilience, capable of mutating to escape immune detection and re-establishing infectious capabilities despite new vaccine rollouts. Therefore, there is a ...critical need to identify relatively immutable epitopes on the SARS-CoV-2 virion that are resistant to future mutations the virus may accumulate. While hACE2 has been identified as the receptor that mediates SARS-CoV-2 susceptibility, it is only modestly expressed in lung tissue. C-type lectin receptors like DC-SIGN can act as attachment sites to enhance SARS-CoV-2 infection of cells with moderate or low hACE2 expression. We developed an easy-to-implement assay system that allows for the testing of SARS-CoV-2 trans-infection. Using our assay, we assessed how SARS-CoV-2 Spike S1-domain glycans and spike proteins from different strains affected the ability of pseudotyped lentivirions to undergo DC-SIGN-mediated trans-infection. Through our experiments with seven glycan point mutants, two glycan cluster mutants and four strains of SARS-CoV-2 spike, we found that glycans N17 and N122 appear to have significant roles in maintaining COVID-19′s infectious capabilities. We further found that the virus cannot retain infectivity upon the loss of multiple glycosylation sites, and that Omicron BA.2 pseudovirions may have an increased ability to bind to other non-lectin receptor proteins on the surface of cells. Taken together, our work opens the door to the development of new therapeutics that can target overlooked epitopes of the SARS-CoV-2 virion to prevent C-type lectin-receptor-mediated trans-infection in lung tissue.
Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for ...C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.
The use of autologous tolerogenic dendritic cells (tolDC) has become a promising strategy to re-establish immune tolerance in autoimmune diseases. Among the different strategies available, the use of ...vitamin D3 for the generation of tolDC (VitD3-tolDC) has been widely tested because of their immune regulatory properties. To identify molecules and pathways involved in the generation of VitD3-tolDC, we established an easy and fast gene silencing method based on the use of Viromer blue to introduce siRNA into monocytes on day 1 of culture differentiation. The analysis of the effect of CD209 (DC-SIGN) and CD115 (CSF1R) down-modulation on the phenotype and functionality of transfected VitD3-tolDC revealed a partial role of CD115 in their tolerogenicity. Further investigations showed that CSF1R-CSF1 signaling is involved in the induction of cell metabolic reprogramming, triggering glycolysis to produce high amounts of lactate, a novel suppressive mechanism of T cell proliferation, recently found in autologous tolerogenic dendritic cells (ATDCs).
Summary
In the pathological process of acute kidney injury (AKI), innate immune receptors are essential in inflammatory response modulation; however, the precise molecular mechanisms are still ...unclear. Our study sought to demonstrate the inflammatory response mechanisms in renal tubular epithelial cells via Toll‐like receptor‐4 (TLR‐4) and dendritic cell‐specific intercellular adhesion molecule 3‐grabbing non‐integrin 1 (DC‐SIGN) signalling. We found that DC‐SIGN exhibited strong expression in renal tubular epithelial cells of human acute renal injury tissues. DC‐SIGN protein expression was increased significantly when renal tubular epithelial cells were exposed to lipopolysaccharide (LPS) for a short period. Furthermore, DC‐SIGN was involved in the activation of p65 by TLR‐4, which excluded p38 and c‐Jun N‐terminal kinases (JNK). Interleukin (IL)‐6 and tumour necrosis factor (TNF)‐α expression was decreased after DC‐SIGN knock‐down, and LPS induced endogenous interactions and plasma membrane co‐expression between TLR‐4 and DC‐SIGN. These results show that DC‐SIGN and TLR‐4 interactions regulate inflammatory responses in renal tubular epithelial cells and participate in AKI pathogenesis.
DC‐SIGN and TLR4 interactions regulate the inflammatory response mediated by renal tubular epithelial cells and that this response participates in the AKI pathogenesis.
Bovine lactoferrin (bLF) presents in milk and has been shown to inhibit several viral infections. Effective drugs are unavailable for the treatment of dengue virus (DENV) infection. In this study, we ...evaluated the antiviral effect of bLF against DENV infection in vivo and in vitro. Bovine LF significantly inhibited the infection of the four serotypes of DENV in Vero cells. In the time-of-drug addition test, DENV-2 infection was remarkably inhibited when bLF was added during or prior to the occurrence of virus attachment. We also revealed that bovine LF blocks binding between DENV-2 and the cellular membrane by interacting with heparan sulfate (HS), dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), and low-density lipoprotein receptors (LDLR). In addition, bLF inhibits DENV-2 infection and decreases morbidity in a suckling mouse challenge model. This study supports the finding that bLF may inhibit DENV infection by binding to the potential DENV receptors.
Leprosy, caused by Mycobacterium leprae, is a public health problem in Brazil that affects peripheral nerves, resulting in physical disabilities. During host-pathogen interactions, the immune ...response determines leprosy outcomes from a localised (paucibacillary) form to a disseminated (multibacillary) form. The recognition of M. leprae involves the DC-SIGN receptor, which is present on the dendritic cells (DCs) and participates in immune activation.
To evaluate the association of polymorphisms in the promoter region of the gene encoding DC-SIGN (CD209) and the clinical form of leprosy, and to investigate its functional effects.
The study population included 406 leprosy patients from an endemic area in Brazil 310 multibacillary (MB); 96 paucibacillary (PB). A functional evaluation based on the effects of the single nucleotide variant (SNV) associated with PB leprosy on the specific immune response was also performed.
The GA genotype and the presence of the A allele of rs735240 (-939G>A) were associated with PB leprosy OR: 2.09 (1.18-3.69) and 1.84 (1.07-3.14), respectively. Carriers of the A allele showed reduced expression of CD209 and TGF-β1 in leprosy lesions in comparison with individuals with GG genotype, in addition to a higher response to the Mitsuda test.
These data suggest that rs735240 influences the immune response against M. leprae and clinical presentation of leprosy.
DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status ...remain poorly defined. Here, we identify a microRNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/− mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a.
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•miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation•miR-181a limits DC-SIGN+ mo-DC responsiveness to inflammatory stimuli•miR-181a fine-tunes terminal mo-DC differentiation by modulating ERK-MAPK signaling
DC-SIGN+ mo-DCs play important roles in bacterial infections and inflammatory diseases, but the factors regulating differentiation and activation remain poorly defined. Lim et al. show that miR-181a simultaneously fine-tunes DC-SIGN+ mo-DC differentiation/activation by promoting ERK-MAPK signaling, which sustains DC-SIGN expression and limits its responsiveness to TLR4 triggering and inflammatory stimuli.
The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic ...breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1-9 and Ang 1-7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.
Background and aims
In this observational cohort study, we assessed the prognostic value of DC‐SIGN+ cells in the pathogenesis and progression of IgA nephropathy (IgAN).
Methods and results
A total ...of 139 adult IgAN patients were enrolled into this study from June 2009 to June 2010. We characterised DC‐SIGN+ cells by immunohistochemistry or immunofluorescence in renal biopsy tissue. Correlations between the DC‐SIGN, intercellular adhesion molecule 3 (ICAM‐3), CD4 and CD8 were evaluated. Patients were classified into the DC‐SIGNhigh and DC‐SIGNlow groups. Depending on an average of 100‐month follow‐up, the predictive value of DC‐SIGN+ cells in IgAN progression was analysed. DC‐SIGN+ cells were found frequently in IgAN kidneys while rarely observed in normal kidneys, and almost all DC‐SIGN+ cells expressed MHC‐II. We also found that DC‐SIGN+ cells were adjacent to ICAM‐3‐positive CD4+ and CD8+ lymphocytes. The density of DC‐SIGN+ cells was positively and linearly correlated with the density of ICAM‐3+ cells, CD4+ cells and CD8+ cells in renal biopsy tissues. In the DC‐SIGNhigh group, the degree of renal lesion and inflammatory cell infiltration was more severe compared to the DC‐SIGNlow group. Patients in the DC‐SIGNhigh group also had increased incidences of deteriorating renal function during the follow up compared to patients in the DC‐SIGNlow group.
Conclusions
DC‐SIGN+ cells probably served as a potential contributor to exacerbate local inflammatory response. The density of DC‐SIGN+ cells was associated with the severity of renal lesions of the patients. High renal DC‐SIGN+ cell density might be used as a predictor of poor prognosis in patients with IgAN.
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