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Uncontrolled severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection is closely related to disorders of the innate immune and delayed adaptive immune systems. Dendritic cells (DCs) “bridge” innate immunity and adaptive immunity. DCs have important roles in defending against SARS-CoV-2 infection. In this review, we summarize the latest research concerning the role of DCs in SARS-CoV-2 infection. We focus on the complex interplay between DCs and SARS-CoV-2: pyroptosis-induced activation; activation of the renin–angiotensin–aldosterone system; and activation of dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin. We also discuss the decline in DC number, the impaired antigen-presentation capability, and the reduced production of type-I interferon of DCs in severe SARS-CoV-2 infection. In addition, we discuss the potential mechanisms for pathological activation of DCs to understand the pattern of SARS-CoV-2 infection. Lastly, we provide a brief overview of novel vaccination and immunotherapy strategies based on DC targeting to overcome SARS-CoV-2 infection.

Hypoglycemia is associated with cardiovascular events reflected by platelet abnormalities. We hypothesized that sequential endothelial changes may occur during hypoglycemia that may enhance cardiovascular risk. In type 2 diabetes (T2D) (n = 23) and controls (n = 23), blood SOMAscan proteomic analysis of endothelial proteins at baseline, insulin-induced hypoglycemia and post hypoglycemia to 24 h were examined using repeated-measures linear mixed modeling with a prospective parallel study design. Most endothelial proteins that changed over time did not differ between groups. Baseline levels of P-selectin, plasminogen activator inhibitor-1 (PAI-1; serpine-1), E-selectin and angiopoietin-1 (ANGPT1) were significantly higher, whilst cadherin-5 was lower in T2D. Several proteins exhibited changes versus baseline in both T2D and controls. Under hypoglycemia, decreases in cadherin-5 and soluble angiopoietin-1 receptor (sTie-2) were observed, with increased P-selectin, intercellular adhesion molecule-3 (ICAM3), ANGPT1 and PAI-1. Post hypoglycemia, decreased cadherin-5 and ICAM5 were observed at 2 h and PAI-1 at 4 h, as well as increases in P-selectin at 30 min, 1 h and 24 h and ICAM3 at 24 h. Post hypoglycemia, E-selectin, P-selectin and ICAM3 were significantly lower in T2D patients at 2 h, while PAI-1 was significantly lower at 4 h and ICAM3 was significantly lower at 24 h. Baseline endothelial proteins differed between T2D and controls, which may suggest local endothelial inflammatory activation leading to a pro-thrombotic, destabilized vascular phenotype characteristic of diabetic vasculopathy. Hypoglycemia may exacerbate this towards a pro-adhesive and pro-thrombotic phenotype, worsening endothelial dysfunction.

Asthma is a heterogeneous disease that affects approximately 300 million people worldwide, largely in developed countries. The etiology of the disease is poorly understood, but is likely to involve specific innate and adaptive responses to inhaled microbial components that are found in allergens. Fungal-derived allergens represent a major contributing factor in the initiation, persistence, exacerbation, and severity of allergic asthma. C-type lectin like receptors, such as dectin-1, dectin-2, DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, and mannose receptor, recognize many fungal-derived allergens and other structurally similar allergens derived from house dust mites (HDM). In some cases, the fungal derived allergens have been structurally and functionally identified alongside their respective receptors in both humans and mice. In this review, we discuss recent understanding on how selected fungal and HDM derived allergens as well as their known or unknown receptors shape allergic airway diseases.

Fluid resuscitation via colon (FRVC) is a complementary therapeutic procedure for early-stage cases of severe acute pancreatitis (SAP). The expression of intestinal dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) regulates systemic inflammation. This study aimed to investigate the effect of FRVC on the expression of DC-SIGN in the colon tissue of SAP rats and its effect on the early response of systemic inflammatory and multiple organ injury. SAP was induced in rats via retrograde injection of sodium taurocholate into the biliopancreatic duct. DC-SIGN expression of appeared in the proximal and distal colon. Histological characteristics and inflammatory cytokines were examined to compare the effect of FRVC and intravenous fluid resuscitation (IVFR). The results showed that DC-SIGN expression in the proximal colon increased in a time-dependent manner in the early-stage of SAP rats. FRVC inhibited DC-SIGN expression in the proximal colon. Both FRVC and IVFR alleviated histological injuries of the pancreas and colon. However, FRVC had an advantage over IVFR in alleviating lung injury and reducing serum TNF-α, IL-6 and LPS. These results suggest that FRVC treatment might help suppress systemic inflammation and prevent subsequent organ failure in early-stage SAP rats likely through inhibiting DC-SIGN expression in the proximal colon.

Key Points Glycans that are present on glycoproteins often have a pivotal role in protein folding, trafficking and protection against degradation, the efficient operation of the innate immune system and, as in the case of pathogens such as HIV, escape by the immune system. There exists a wide range of carbohydrate-binding agents (CBAs), including lectins and synthetic small-size non-peptidic agents, and their molecular interactions with carbohydrates are well described. A number of CBAs, with a preference for mannose and/or N -acetylglucosamine (GlcNAc) recognition have been shown to inhibit HIV infections by blocking the viral entry process. They have also been shown to be active against other viruses such as human hepatitis C virus (HCV), coronavirus and influenza virus. When HIV is exposed to CBAs, virus escape eventually occurs predominantly by deleting its glycans on the viral envelope glycoprotein gp120. It has been shown that such mutant virus strains have an increased sensitivity to neutralizing antibodies. Numerous other pathogens, including HCV, bacteria such as Mycobacterium tuberculosis and Helicobacter pylori , parasites such as Leishmania spp. or fungi such as Aspergillus spp. and Candida spp., efficiently use the C-type lectin dendritic-cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) present on DCs for transmission and/or immune suppression. These pathogens may represent prime candidate compounds that can be exposed to CBAs in an attempt to interrupt the infection or transmission process in the host. CBA therapy of HIV (and possibly other pathogens) may represent a therapeutic approach with a dual mechanism of action: the direct inhibition of virus capture, transmission and entry into its target cells; and the recruitment of the immune system after glycan deletions occur under CBA pressure, uncovering previously hidden immunogenic epitopes on the viral envelope. Carbohydrate-binding agents (CBAs) are a family of diverse molecules that can bind to specific glycan structures on viruses or target cells. Jan Balzarini describes a new antiviral mechanism that is based on the specific interaction of CBAs with the glycans that are present on viral-envelope glycoproteins. Several chronic viral infections (such as HIV and hepatitis C virus) are highly prevalent and are a serious health risk. The adaptation of animal viruses to the human host, as recently exemplified by influenza viruses and the severe acute respiratory syndrome coronavirus, is also a continuous threat. There is a high demand, therefore, for new antiviral lead compounds and novel therapeutic concepts. In this Review, an original therapeutic concept for suppressing enveloped viruses is presented that is based on a specific interaction of carbohydrate-binding agents (CBAs) with the glycans present on viral-envelope glycoproteins. This approach may also be extended to other pathogens, including parasites, bacteria and fungi.

Background: Diabetes, particularly type 2 diabetes (T2D), is linked with an increased risk of developing coronary heart disease (CHD). The present study aimed to evaluate potential circulating biomarkers of CHD by adopting a targeted proteomic approach based on proximity extension assays (PEA). Methods: The study was based on 30 patients with both T2D and CHD (group DC), 30 patients with T2D without CHD (group DN) and 29 patients without diabetes but with a diagnosis of CHD (group NC). Plasma samples were analyzed using PEA, with an Olink Target 96 cardiometabolic panel expressed as normalized protein expression (NPX) units. Results: Lysosomal Pro-X carboxypeptidase (PRCP), Liver carboxylesterase 1 (CES1), Complement C2 (C2), and Intercellular adhesion molecule 3 (ICAM3) were lower in the DC and NC groups compared with the DN groups. Lithostathine-1-alpha (REG1A) and Immunoglobulin lambda constant 2 (IGLC2) were found higher in the DC group compared to DN and NC groups. ROC analysis suggested a significant ability of the six proteins to distinguish among the three groups (whole model test p < 0.0001, AUC 0.83–0.88), with a satisfactory discriminating performance in terms of sensitivity (77–90%) and specificity (70–90%). A possible role of IGLC2, PRCP, and REG1A in indicating kidney impairment was found, with a sensitivity of 92% and specificity of 83%. Conclusions: The identified panel of six plasma proteins, using a targeted proteomic approach, provided evidence that these parameters could be considered in the chronic evolution of T2D and its complications.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly characterized by eosinophil- and T helper 2 cell (Th2)-biased inflammation. Integrins and intercellular adhesion molecules (ICAMs) are superfamilies of cell adhesion molecules (CAMs) that facilitate the recruitment and trafficking of immune cells and have been implicated in coordinating eosinophil and Th2 cell adhesion and signaling in asthma. The roles of CAMs in CRSwNP, however, remain poorly understood. The purpose of this study was to characterize the systemic and local expression of CAMs and identify which CAMs are potentially involved in CRSwNP pathology. A prospective observational study was conducted using peripheral blood and anterior ethmoid tissues of patients with CRSwNP (n=32) and controls (n=15). Multiplex gene analysis and Pearson correlations were performed to identify associations between systemically and locally expressed CAMs. Based on the gene expression results, immunohistochemical evaluation and quantification of cells expressing integrins ITGAM, ITGAX, and ITGB2, as well as ICAM-3 in sinonasal tissues were conducted to compare local protein expression patterns. Integrin and ICAM genes were significantly elevated in the blood ( <0.001 to <0.05) and sinuses ( <0.0003 to <0.05) of patients with CRSwNP compared to controls. Strong positive correlations of genes expressed in the blood ( <0.01 to <0.05) and sinuses ( <0.01) were observed between , and . ITGAM-, ITGB2-, ICAM-3-, and ICAM-3/ITGB2-positive cell counts were significantly increased in CRSwNP compared to controls ( <0.0001 to <0.04), and a positive correlation between ICAM-3/ITGB2- and ITGAM-positive cell counts was observed ( <0.02). The systemic and local expression of ITGAM, ITGB2, and ICAM-3 is significantly upregulated in CRSwNP, suggesting that integrin complex ITGAM/ITGB2 and ICAM-3 serve a potential role in inflammation-mediated signaling in CRSwNP.

Little is known about circulating biomarkers of vascular injury in relation to cardiovascular disease risk. Thus, we evaluated associations between six novel markers (E-Selectin, P-Selectin, thrombomodulin, thrombopoietin, intercellular adhesion molecule 3 and GPIIb/IIIa) and established cardiovascular risk factors as well as the risk of myocardial infarction (MI) in a population-based study. Biomarkers were measured in pre-diagnostic plasma samples of a case-cohort subset of EPIC-Heidelberg (incident MI cases: n = 369, random sub-cohort: n = 2,418). Generalized Linear models were used to analyse cross-sectional associations between biomarkers and cardiovascular risk factors. Multivariable Cox Regression analyses were carried out to obtain Hazard Ratios (HRs) of MI across quartiles of biomarkers levels. Cross-sectional analyses showed that sex, smoking, alcohol consumption, diabetes and exogenous hormone use were associated with biomarker levels. However, while fibrinogen was associated with MI risk (HR per standard deviation: 2.97 [95% confidence interval: 1.61, 5.46]), none of the six novel biomarkers was associated with MI risk after multivariable adjustment. In a population-based cohort, biomarkers of vascular injury were associated with established cardiovascular risk factors, but not MI risk. The tested biomarkers may reflect pathophysiological alterations in cardiovascular disease development rather than constituting independent MI risk factors.

Dendritic cells (DC), present in the skin, are the first target cells of dengue virus (DENV). Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) is present on DC and recognizes N-glycosylation sites on the E-glycoprotein of DENV. Thus, the DC-SIGN/E-glycoprotein interaction can be considered as an important target for inhibitors of viral replication. We evaluated various carbohydrate-binding agents (CBAs) against all four described serotypes of DENV replication in Raji/DC-SIGN(+) cells and in monocyte-derived DC (MDDC). A dose-dependent anti-DENV activity of the CBAs Hippeastrum hybrid (HHA), Galanthus nivalis (GNA) and Urtica dioica (UDA), but not actinohivin (AH) was observed against all four DENV serotypes as analyzed by flow cytometry making use of anti-DENV antibodies. Remarkably, the potency of the CBAs against DENV in MDDC cultures was significantly higher (up to 100-fold) than in Raji/DC-SIGN(+) cells. Pradimicin-S (PRM-S), a small-size non-peptidic CBA, exerted antiviral activity in MDDC but not in Raji/DC-SIGN(+) cells. The CBAs act at an early step of DENV infection as they bind to the viral envelope of DENV and subsequently prevent virus attachment. Only weak antiviral activity of the CBAs was detected when administered after the virus attachment step. The CBAs were also able to completely prevent the cellular activation and differentiation process of MDDC induced upon DENV infection. The CBAs exerted broad spectrum antiviral activity against the four DENV serotypes, laboratory-adapted viruses and low passage clinical isolates, evaluated in Raji/DC-SIGN(+) cells and in primary MDDC.

Dendritic cell specific intracellular adhesion molecule-3 (ICAM-3) grabbing nonintegrin (DC-SIGN), a C-type lectin present on the surface of dendritic cells, mediates the initial interaction of dendritic cells with T cells by binding to ICAM-3. DC-SIGN and DC-SIGNR, a related receptor found on the endothelium of liver sinusoids, placental capillaries, and lymph nodes, bind to oligosaccharides that are present on the envelope of human immunodeficiency virus (HIV), an interaction that strongly promotes viral infection of T cells. Crystal structures of carbohydrate-recognition domains of DC-SIGN and of DC-SIGNR bound to oligosaccharide, in combination with binding studies, reveal that these receptors selectively recognize endogenous high-mannose oligosaccharides and may represent a new avenue for developing HIV prophylactics.