Summary
Endothelial dysfunction leading to vascular leak is the hallmark of severe dengue. Vascular leak typically becomes clinically evident 3–6 days after the onset of illness, which is known as ...the critical phase. This critical phase follows the period of peak viraemia, and lasts for 24–48 hr and usually shows rapid and complete reversal, suggesting that it is likely to occur as a result of inflammatory mediators, rather than infection of the endothelium. Cytokines such as tumour necrosis factor‐α, which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue NS1, a soluble viral protein, has also been shown to disrupt the endothelial glycocalyx and thus contribute to vascular leak, although there appears to be a discordance between the timing of NS1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (PAF) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin‐2 have been shown to be elevated in patients with dengue haemorrhagic fever, exerting their action in part by inducing the activity of phospholipases, which have diverse inflammatory effects including generation of PAF. Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin‐1β through activation of the NLRP3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down‐stream immunological mediator pathways such as PAF may also be beneficial in the treatment of severe disease.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention.
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ...ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
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•Genetic ablation of ILC2s impairs type-2 immunity•MHCII-expressing ILC2s potentiate Th2 responses•IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines•MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion
Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.
Dengue is the most rapidly emerging climate-sensitive infection, and there has been a 10-fold rise in cases over the past 20 years.Severe illness is characterized by vascular leakage, organ ...dysfunction, and severe bleeding which occur due to the direct effects of the viral non-structural protein NS1 and an aberrant host immune response.Dengue NS1 antigen, cytokines such as IL-1β, TNF-α, and IL-6, lipid mediators such as platelet-activating factor (PAF), leukotrienes and prostaglandins, VEGF, chymase, tryptase, and MMP-9 are thought to contribute to endothelial dysfunction.Many mechanisms contribute to liver dysfunction, including prolonged shock that causes hypoxic damage, direct liver cell death due to infection with the virus, and immune-mediated effects.Bleeding following dengue virus infection occurs due to multiple mechanisms including platelet activation by NS1, serotonin, and PAF, accompanied by a wide range of other coagulation abnormalities.
Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being overwhelmed. There are currently no specific treatments for dengue or prognostic markers to identify those who will progress to severe disease. Owing to an increase in the burden of illness and a change in epidemiology, many patients experience severe disease. Our limited understanding of the complex mechanisms of disease pathogenesis has significantly hampered the development of safe and effective treatments, vaccines, and biomarkers. We discuss the molecular mechanisms of dengue pathogenesis, the gaps in our knowledge, and recent advances, as well as the most crucial questions to be answered to enable the development of therapeutics, biomarkers, and vaccines.
Dengue is the most rapidly emerging climate-sensitive infection, and morbidity/mortality and disease incidence are rising markedly, leading to healthcare systems being overwhelmed. There are currently no specific treatments for dengue or prognostic markers to identify those who will progress to severe disease. Owing to an increase in the burden of illness and a change in epidemiology, many patients experience severe disease. Our limited understanding of the complex mechanisms of disease pathogenesis has significantly hampered the development of safe and effective treatments, vaccines, and biomarkers. We discuss the molecular mechanisms of dengue pathogenesis, the gaps in our knowledge, and recent advances, as well as the most crucial questions to be answered to enable the development of therapeutics, biomarkers, and vaccines.
Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen ...challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1(-/-) and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.
The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and host immune factors. Existing published data are not consistent, ...in part related to relatively small sample sizes. We set out to determine possible associations between dengue virus (DEN-V) NS3 specific T cells and cytokine and chemokine levels and the pathogenesis of severe disease in a large cohort of individuals with DHF.
By using ex vivo IFNγ ELISpot assays we determined DENV-NS3 specific responses in patients with varying severity of DHF. Other cytokines produced by DENV-NS3 specific T cells were determined by using multiple bead array analysis (MBAA). We also determined the serum cytokine levels using MBAA, lymphocyte subsets and Annexin V expression of lymphocytes in patients with varying severity of DHF. Of the 112 DHF patients studied, 29 developed shock. Serum IL-10 and IP-10 levels positively and significantly correlated with T cell apoptosis while IL-10 levels inversely correlated with T cell numbers. In contrast, TGFß showed a very significant (P<0.0001) and positive correlation (Spearman's R = 0.65) with the platelet counts, consistent with platelet release. We found that whilst patients with severe dengue had lower total T cell numbers, the DV-NS3 specific T cells persisted and produced high levels of IFNγ but not TNFα, IL-3, IL-13, IL-2, IL-10 or IL-17.
Our data suggest that serum IL-10, TNFα and TGFβ differentially associate with dengue disease severity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dengue and COVID-19: two sides of the same coin Malavige, Gathsaurie Neelika; Jeewandara, Chandima; Ogg, Graham S
Journal of biomedical science,
07/2022, Letnik:
29, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Many countries in Asia and Latin America are currently facing a double burden of outbreaks due to dengue and COVID-19. Here we discuss the similarities and differences between the two infections so ...that lessons learnt so far from studying both infections will be helpful in further understanding their immunopathogenesis and to develop therapeutic interventions.
Although the entry routes of the SARS-CoV-2 and the dengue virus (DENV) are different, both infections result in a systemic infection, with some similar clinical presentations such as fever, headache, myalgia and gastrointestinal symptoms. However, while dengue is usually associated with a tendency to bleed, development of micro and macrothrombi is a hallmark of severe COVID-19. Apart from the initial similarities in the clinical presentation, there are further similarities between such as risk factors for development of severe illness, cytokine storms, endothelial dysfunction and multi-organ failure. Both infections are characterised by a delayed and impaired type I IFN response and a proinflammatory immune response. Furthermore, while high levels of potent neutralising antibodies are associated with protection, poorly neutralising and cross-reactive antibodies have been proposed to lead to immunopathology by different mechanisms, associated with an exaggerated plasmablast response. The virus specific T cell responses are also shown to be delayed in those who develop severe illness, while varying degrees of endothelial dysfunction leads to increased vascular permeability and coagulation abnormalities.
While there are many similarities between dengue and SARS-CoV-2 infection, there are also key differences especially in long-term disease sequelae. Therefore, it would be important to study the parallels between the immunopathogenesis of both infections for development of more effective vaccines and therapeutic interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition associated with a significant health-related and socioeconomic burden, and is characterized by intense ...itch, disruption of the skin barrier, and upregulation of type 2-mediated immune responses. The United Kingdom (UK) has a high prevalence of AD, affecting 11-20% of children and 5-10% of adults. Approximately 2% of all cases of childhood AD in the UK are severe. Despite this, most AD treatments are performed at home, with little contact with healthcare providers or services. Here, we discuss the course of AD, treatment practices, and unmet need in the UK. Although the underlying etiology of the disease is still emerging, AD is currently attributed to skin barrier dysfunction and altered inflammatory responses. Management of AD focuses on avoiding triggers, improving skin hydration, managing exacerbating factors, and reducing inflammation through topical and systemic immunosuppressants. However, there is a significant unmet need to improve the overall management of AD and help patients gain control of their disease through safe and effective treatments. Approaches that target individual inflammatory pathways (e.g. dupilumab, anti-interleukin (IL)-4 receptor α) are emerging and likely to provide further therapeutic opportunities for patient benefit.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although infection with the dengue virus (DENV) causes severe dengue, it causes a mild self-limiting illness in the majority of individuals. There is emerging evidence that an aberrant immune ...response in the initial stages of infection lead to severe disease. Many inflammatory cytokines, chemokines, and lipid mediators are significantly higher in patients with severe dengue compared to those who develop mild infection, during febrile phase of illness. Monocytes, mast cells, and many other cells of the immune system, when infected with the DENV, especially in the presence of poorly neutralizing antibodies, leads to production of pro-inflammatory cytokines and inhibition of interferon signaling pathways. In addition, production of immunosuppressive cytokines such as IL-10 further leads to inhibition of cellular antiviral responses. This dysregulated and aberrant immune response leads to reduced clearance of the virus, and severe dengue by inducing a vascular leak and excessive inflammation due to high levels of inflammatory cytokines. Individuals with comorbid illnesses could be prone to more severe dengue due to low grade endotoxemia, gut microbial dysbiosis and an altered phenotype of innate immune cells. The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes are likely to further act on T cells and B cells leading to an impaired adaptive immune response to the virus. Therefore, in order to identify therapeutic targets for treatment of dengue, it would be important to further characterize these mechanisms in order for early intervention. In this review, we discuss the differences in the innate immune responses in those who progress to develop severe dengue, compared to those with milder disease in order to understand the mechanisms that lead to severe dengue.
The role of NS1-specific antibodies in the pathogenesis of dengue virus infection is poorly understood. Here we investigate the immunoglobulin responses of patients with dengue fever (DF) and dengue ...hemorrhagic fever (DHF) to NS1. Antibody responses to recombinant-NS1 are assessed in serum samples throughout illness of patients with acute secondary DENV1 and DENV2 infection by ELISA. NS1 antibody titres are significantly higher in patients with DHF compared to those with DF for both serotypes, during the critical phase of illness. Furthermore, during both acute secondary DENV1 and DENV2 infection, the antibody repertoire of DF and DHF patients is directed towards distinct regions of the NS1 protein. In addition, healthy individuals, with past non-severe dengue infection have a similar antibody repertoire as those with mild acute infection (DF). Therefore, antibodies that target specific NS1 epitopes could predict disease severity and be of potential benefit in aiding vaccine and treatment design.
Vascular leak is a hallmark of severe dengue, and high leukotriene levels have been observed in dengue mouse models, suggesting a role in disease pathogenesis. We sought to explore their role in ...acute dengue, by assessing levels of urinary LTE4 and urinary histamine in patients with varying severity of acute dengue.
Urinary LTE4, histamine and creatinine were measured by a quantitative ELISA, in healthy individuals (n = 19), patients with dengue fever (DF = 72) and dengue haemorrhagic fever DHF (n = 48). The kinetics of LTE4 and histamine and diurnal variations were assessed in a subset of patients.
Urinary LTE4 levels were significantly higher (p = 0.004) in patients who proceed to develop DHF when compared to patients with DF during early illness (≤ 4 days) and during the critical phase (p = 0.02), which continued to rise in patients who developed DHF during the course of illness. However, LTE4 is unlikely to be a good biomarker as ROCs gave an AUC value of 0.67 (95% CI 0.57 and 0.76), which was nevertheless significant (p = 0.002). Urinary LTE4 levels did not associate with the degree of viraemia, infecting virus serotype and was not different in those with primary vs secondary dengue. Urinary histamine levels were significantly high in patients with acute dengue although no difference was observed between patients with DF and DHF and again did not associate with the viraemia. Interestingly, LTE4, histamine and the viral loads showed a marked diurnal variation in both patients with DF and DHF.
Our data suggest that LTE4 could play a role in disease pathogenesis and since there are safe and effective cysteinyl leukotriene receptor blockers, it would be important to assess their efficacy in reducing dengue disease severity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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