scholarly journals Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue

2020 ◽  
Vol 11 ◽  
Author(s):  
Vinit Upasani ◽  
Carolina Scagnolari ◽  
Federica Frasca ◽  
Nikaïa Smith ◽  
Vincent Bondet ◽  
...  
Keyword(s):  
Single Molecule ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Type I Interferons ◽  
Severe Dengue ◽  
Type I ◽  
Type I Ifn ◽  
Dengue Disease ◽  
Healthy Donors

The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.

scholarly journals Maternal Immunity and Vaccination Influence Disease Severity in Progeny in a Novel Mast Cell-Deficient Mouse Model of Severe Dengue

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 900
Author(s):  
Chinmay Kumar Mantri ◽  
Gayathri Soundarajan ◽  
Wilfried A. A. Saron ◽  
Abhay P. S. Rathore ◽  
Sylvie Alonso ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Severity ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Type I ◽  
Complex Interactions ◽  
Dependent Model

Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to a deficiency in Type-I and II IFN receptors for studying dengue virus (DENV) infection. We used this model to understand the influence of MCs in a maternal antibody-dependent model of severe dengue, where offspring born to DENV-immune mothers are challenged with a heterologous DENV serotype. Mice lacking both MCs and IFN receptors were found susceptible to primary DENV infection and showed morbidity and mortality. When these mice were immunized, pups born to DENV-immune mothers were found to be protected for a longer duration from a heterologous DENV challenge. In the absence of MCs and type-I interferon signaling, IFN-γ was found to protect pups born to naïve mothers but had the opposite effect on pups born to DENV-immune mothers. Our results highlight the complex interactions between MCs and IFN-signaling in influencing the role of maternal antibodies in DENV-induced disease severity.

scholarly journals Serum IL-18 Is a Potential Biomarker for Predicting Severe Dengue Disease Progression

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Josephine Diony Nanda ◽  
Chiau-Jing Jung ◽  
Rahmat Dani Satria ◽  
Ming-Kai Jhan ◽  
Ting-Jing Shen ◽  
...  
Keyword(s):  
Acute Phase ◽  
Disease Onset ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Dengue Disease ◽  
Potential Biomarker ◽  
Tnf Α ◽  
Principal Finding

Background. Dengue virus (DENV) infection is the most common arboviral disease that affects tropical and subtropical regions. Based on the clinical hallmarks, the different severities of patients range from mild dengue fever (MDF) to severe dengue diseases (SDDs) and include dengue hemorrhagic fever or dengue shock syndrome. These are commonly associated with cytokine release syndrome (CRS). The types and levels of cytokines/chemokines, which are suppressed or enhanced, are varied, indicating CRS’s pathogenic and host defensive effects. Principal Finding. In this study, we created an integrated and precise multiplex panel of cytokine/chemokine assays based on our literature analysis to monitor dengue CRS. A 24-plex panel of cytokines/chemokines was evaluated to measure the plasma levels of targeting factors in dengue patients with an MDF and SDD diagnosis without or with comorbidities. As identified in sixteen kinds of cytokines/chemokines, ten were significantly ( P < 0.05 ) (10/16) increased, one was significantly ( P < 0.01 ) (1/16) decreased, and five were potentially (5/16) altered in all dengue patients ( n = 30 ) in the acute phase of disease onset. Compared to MDF, the levels of IL-8 (CXCL-8) and IL-18 in SDD were markedly ( P < 0.05 ) increased, accompanied by positively increased IL-6 and TNF-α and decreased IFN-γ and RANTES. With comorbidities, SDD significantly ( P < 0.01 ) portrayed elevated IL-18 accompanied by increased IL-6 and decreased IFN-α2 and IL-12. In addition, decreased platelets were significantly ( P < 0.05 ) associated with increased IL-18. Significance. These results demonstrate an efficient panel of dengue cytokine/chemokine assays used to explore the possible level of CRS during the acute phase of disease onset; also, we are the first to report the increase of IL-18 in severe dengue with comorbidity compared to severe dengue without comorbidity and mild dengue.

scholarly journals Pathogenesis of Dengue: Dawn of a New Era

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1353 ◽  
Author(s):  
Scott B. Halstead
Keyword(s):  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Structural Protein ◽  
New Era ◽  
Dengue Disease ◽  
Toll Receptor

Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings

scholarly journals A Novel Role for the Regulatory Nod-Like Receptor NLRP12 in Anti-Dengue Virus Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingyu Li ◽  
Zhuo Dong ◽  
Yan Liu ◽  
Weifeng Song ◽  
Jieying Pu ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Poly I:C ◽  
Severe Illness ◽  
Human Macrophage ◽  
Type I ◽  
Zikv Infection ◽  
Type I Ifns

Dengue Virus (DENV) infection can cause severe illness such as highly fatality dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Innate immune activation by Nod-like receptors (NLRs) is a critical part of host defense against viral infection. Here, we revealed a key mechanism of NLRP12-mediated regulation in DENV infection. Firstly, NLRP12 expression was inhibited in human macrophage following DENV or other flaviviruses (JEV, YFV, ZIKV) infection. Positive regulatory domain 1 (PRDM1) was induced by DENV or poly(I:C) and suppressed NLRP12 expression, which was dependent on TBK-1/IRF3 and NF-κB signaling pathways. Moreover, NLRP12 inhibited DENV and other flaviviruses (JEV, YFV, ZIKV) replication, which relied on the well-conserved nucleotide binding structures of its NACHT domain. Furthermore, NLRP12 could interact with heat shock protein 90 (HSP90) dependent on its Walker A and Walker B sites. In addition, NLRP12 enhanced the production of type I IFNs (IFN-α/β) and interferon-stimulated genes (ISGs), including IFITM3, TRAIL and Viperin. Inhibition of HSP90 with 17-DMAG impaired the upregulation of type I IFNs and ISGs induced by NLRP12. Taken together, we demonstrated a novel mechanism that NLRP12 exerted anti-viral properties in DENV and other flaviviruses (JEV, YFV, ZIKV) infection, which brings up a potential target for the treatment of DENV infection.

scholarly journals Detection of interferon alpha protein reveals differential levels and cellular sources in disease

2017 ◽  
Vol 214 (5) ◽  
pp. 1547-1555 ◽  
Author(s):  
Mathieu P. Rodero ◽  
Jérémie Decalf ◽  
Vincent Bondet ◽  
David Hunt ◽  
Gillian I. Rice ◽  
...  
Keyword(s):  
Single Molecule ◽  
Lupus Erythematosus ◽  
Clinical Severity ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Healthy Donors ◽  
Cellular Source ◽  
Digital Elisa

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

scholarly journals Cytokine IL-12, Dengue in children: analysis of a unique relationship

2018 ◽  
Vol 5 (3) ◽  
pp. 1109
Author(s):  
Rakesh Manoharan ◽  
Umapathy Pasupathy ◽  
Latha Ravichandran ◽  
Elayaraja Sivaprakasam ◽  
Srinivasan V. ◽  
...  
Keyword(s):  
Clinical Features ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Study Groups ◽  
Denv Infection ◽  
Warning Signs ◽  
Severe Dengue ◽  
Potential Biomarker ◽  
Paediatric Age ◽  
Dengue With Warning Signs

Background: Dengue is a mosquito borne viral infection caused by one of the four serotypes of dengue viruses (DENV1-DENV4). The consequences of DENV infection range from asymptomatic condition, dengue fever (DF), or severe forms, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The host immune responses have been considered as the major factor responsible for dengue pathogenesis. In this study, the cytokine IL-12 is reviewed for its utility as potential biomarker of severe dengue disease.Methods: 120 children of paediatric age group with either dengue NS1 antigen or dengue IgM positive were included. Cases were classified as uncomplicated dengue (dengue without warning signs) and complicated dengue (dengue with warning signs and severe dengue). Clinical features and IL-12 (ELISA KIT) levels were analyzed in the study population.Results: Analysis of clinical features among the study groups revealed children with complicated dengue had persistent vomiting (95%), abdominal pain (80%), decreased urine output (50%), bleeding manifestations (83.3%), Hepatomegaly (70%) Haemoconcentration with concurrent thrombocytopenia (93.3%), altered coagulation profile (28.3%), ICU stay (54.7%), leukocytosis (15%), leucopoenia (66.6%) normal leucocytes, (18.4%). Analysis of IL-12 levels revealed children with complicated dengue showed significant elevation compared to controls and uncomplicated dengue.Conclusions: In our study IL-12 levels were significantly higher in complicated dengue patients in comparison with uncomplicated dengue patients as well as normal control population.

scholarly journals Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

2020 ◽  
Vol 8 (6) ◽  
pp. 891
Author(s):  
Yen-Chung Lai ◽  
Chiao-Hsuan Chao ◽  
Trai-Ming Yeh
Keyword(s):  
Migration Inhibitory Factor ◽  
Therapeutic Target ◽  
Macrophage Migration Inhibitory Factor ◽  
Critical Factor ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Inhibitory Factor ◽  
Severe Dengue ◽  
Macrophage Migration ◽  
Dengue Disease

Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). Although the cytokine storm has been revealed as a critical factor in dengue disease, the limited understanding of dengue immunopathogenesis hinders the development of effective treatments. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that mediates diverse immune responses, and the serum level of MIF positively correlates with disease severity in patients with dengue. MIF is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. In this paper, the pathogenic roles of MIF and the regulation of MIF secretion during DENV infection are reviewed. Furthermore, whether MIF is a potential therapeutic target against DENV infection is also discussed.

scholarly journals Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

2020 ◽  
Vol 5 (49) ◽  
pp. eabd1554 ◽  
Author(s):  
Jeong Seok Lee ◽  
Seongwan Park ◽  
Hye Won Jeong ◽  
Jin Young Ahn ◽  
Seong Jin Choi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Severe Influenza ◽  
Healthy Donors ◽  
Classical Monocytes

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1β-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.

scholarly journals Cells in Dengue Virus Infection In Vivo

2010 ◽  
Vol 2010 ◽  
pp. 1-15 ◽  
Author(s):  
Sansanee Noisakran ◽  
Nattawat Onlamoon ◽  
Pucharee Songprakhon ◽  
Hui-Mien Hsiao ◽  
Kulkanya Chokephaibulkit ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Emerging Infectious Diseases ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Severe Dengue ◽  
Dengue Virus Infection ◽  
Dengue Disease

Dengue has been recognized as one of the most important vector-borne emerging infectious diseases globally. Though dengue normally causes a self-limiting infection, some patients may develop a life-threatening illness, dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). The reason why DHF/DSS occurs in certain individuals is unclear. Studies in the endemic regions suggest that the preexisting antibodies are a risk factor for DHF/DSS. Viremia and thrombocytopenia are the key clinical features of dengue virus infection in patients. The amounts of virus circulating in patients are highly correlated with severe dengue disease, DHF/DSS. Also, the disturbance, mainly a transient depression, of hematological cells is a critical clinical finding in acute dengue patients. However, the cells responsible for the dengue viremia are unresolved in spite of the intensive efforts been made. Dengue virus appears to replicate and proliferate in many adapted cell lines, but these in vitro properties are extremely difficult to be reproduced in primary cells or in vivo. This paper summarizes reports on the permissive cells in vitro and in vivo and suggests a hematological cell lineage for dengue virus infection in vivo, with the hope that a new focus will shed light on further understanding of the complexities of dengue disease.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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