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 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 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 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 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 Aggressive organ penetration and high vector transmissibility of epidemic dengue virus-2 Cosmopolitan genotype in a transmission mouse model

2021 ◽  
Vol 17 (3) ◽  
pp. e1009480
Author(s):  
Jhe-Jhih Lin ◽  
Pei-Jung Chung ◽  
Shih-Syong Dai ◽  
Wan-Ting Tsai ◽  
Yu-Feng Lin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Dengue Virus ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
International Travel ◽  
Type I ◽  
Virulence Determinants ◽  
Transmission Cycle ◽  
Dengue Outbreaks ◽  
Large Outbreak

Dengue virus (DENV) causes dengue fever and severe hemorrhagic fever in humans and is primarily transmitted by Aedes aegypti and A. albopictus mosquitoes. The incidence of DENV infection has been gradually increasing in recent years due to global urbanization and international travel. Understanding the virulence determinants in host and vector transmissibility of emerging epidemic DENV will be critical to combat potential outbreaks. The DENV serotype 2 (DENV-2), which caused a widespread utbreak in Taiwan in 2015 (TW2015), is of the Cosmopolitan genotype and is hylogenetically related to the virus strain linked to another large outbreak in Indonesia in 2015. We found that the TW2015 virus was highly virulent in type I and type II interferon-deficient mice, with robust replication in spleen, lung, and intestine. The TW2015 virus also had high transmissibility to Aedes mosquitoes and could be effectively spread in a continuous mosquitoes-mice-mosquitoes-mice transmission cycle. By making 16681-based mutants carrying different segments of the TW2015 virus, we identified structural pre-membrane (prM) and envelope (E) genes as key virulence determinants in the host, with involvement in the high transmissibility of the TW2015 virus in mosquitoes. The transmission mouse model will make a useful platform for evaluation of DENV with high epidemic potential and development of new strategies against dengue outbreaks.

scholarly journals IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

Science ◽  
2017 ◽  
Vol 355 (6323) ◽  
pp. 395-398 ◽  
Author(s):  
Taia T. Wang ◽  
Jaturong Sewatanon ◽  
Matthew J. Memoli ◽  
Jens Wrammert ◽  
Stylianos Bournazos ◽  
...  
Keyword(s):  
Risk Factor ◽  
Disease Severity ◽  
Significant Risk ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Significant Risk Factor ◽  
Denv Infection ◽  
Igg Antibodies ◽  
Igg1 Subclass

Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.

scholarly journals The Abstruse Side of Type I Interferon Immunotherapy for COVID-19 Cases with Comorbidities

2021 ◽  
Vol 1 (1) ◽  
pp. 49-59
Author(s):  
Selvakumar Subbian
Keyword(s):  
Infectious Diseases ◽  
Disease Severity ◽  
Type I Interferon ◽  
Host Factors ◽  
Type I ◽  
The Novel ◽  
Inflammatory Drugs ◽  
Precautionary Measures ◽  
Inducible Genes

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.

The Role of Cytokines in Activation of Coagulation and Fibrinolysis in Dengue Shock Syndrome

2002 ◽  
Vol 87 (01) ◽  
pp. 42-46 ◽  
Author(s):  
Catharina Suharti ◽  
Eric van Gorp ◽  
Tatty Setiati ◽  
Robert Djokomoeljanto ◽  
C. Hack ◽  
...  
Keyword(s):  
Early Stage ◽  
Dengue Shock Syndrome ◽  
Severe Dengue ◽  
Prospective Clinical Study ◽  
Bacterial Sepsis ◽  
Activation Markers ◽  
Discharge From Hospital ◽  
Necrosis Factor ◽  
D Dimer

SummaryIn a prospective clinical study of 50 patients with Dengue Shock Syndrome (DSS), we investigated the association of tumor necrosis factor-a (TNF-a), interleukin-1f3 (IL-1f3), IL-1 receptor antagonist (IL-1Ra), and IL-6 with activation markers of coagulation (F1+2 and TATc) and fibrinolysis (t-PA, PAPc, and D-dimer). We found that TNF-a, IL-1f3 and Il-1Ra, but not IL-6, concentrations were elevated in the circulation during the early stage of infection and at discharge from hospital. TNF-a was significantly associated with D-dimer, an activation marker of fibrinolysis (p < 0.003), but not with activation markers of coagulation. IL-1f3 was significantly associated with t-PA (p < 0.03). IL-1Ra was significantly associated with F1+2, TATc (p < 0.04 and p < 0.02, respectively), whereas IL-6 was significantly associated with both, activation markers of coagulation (F1+2; p < 0.03) and fibrinolysis (PAPc; p = 0.002). Our data are in line with studies in bacterial sepsis. In severe dengue virus infection the same cytokines are involved in the onset and regulation of hemostasis.

scholarly journals Dengue Virus Targets Nrf2 for NS2B3-Mediated Degradation Leading to Enhanced Oxidative Stress and Viral Replication

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Matteo Ferrari ◽  
Alessandra Zevini ◽  
Enrico Palermo ◽  
Michela Muscolini ◽  
Magdalini Alexandridi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dengue Virus ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Progressive Increase ◽  
Severe Dengue ◽  
Oxygen Species

ABSTRACT Dengue virus (DENV) is a mosquito-borne virus that infects upward of 300 million people annually and has the potential to cause fatal hemorrhagic fever and shock. While the parameters contributing to dengue immunopathogenesis remain unclear, the collapse of redox homeostasis and the damage induced by oxidative stress have been correlated with the development of inflammation and progression toward the more severe forms of disease. In the present study, we demonstrate that the accumulation of reactive oxygen species (ROS) late after DENV infection (>24 hpi) resulted from a disruption in the balance between oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. The DENV NS2B3 protease complex strategically targeted Nrf2 for degradation in a proteolysis-independent manner; NS2B3 licensed Nrf2 for lysosomal degradation. Impairment of the Nrf2 regulator by the NS2B3 complex inhibited the antioxidant gene network and contributed to the progressive increase in ROS levels, along with increased virus replication and inflammatory or apoptotic gene expression. By 24 hpi, when increased levels of ROS and antiviral proteins were observed, it appeared that the proviral effect of ROS overcame the antiviral effects of the interferon (IFN) response. Overall, these studies demonstrate that DENV infection disrupts the regulatory interplay between DENV-induced stress responses, Nrf2 antioxidant signaling, and the host antiviral immune response, thus exacerbating oxidative stress and inflammation in DENV infection. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen that threatens 2.5 billion people in more than 100 countries annually. Dengue infection induces a spectrum of clinical symptoms, ranging from classical dengue fever to severe dengue hemorrhagic fever or dengue shock syndrome; however, the complexities of DENV immunopathogenesis remain controversial. Previous studies have reported the importance of the transcription factor Nrf2 in the control of redox homeostasis and antiviral/inflammatory or death responses to DENV. Importantly, the production of reactive oxygen species and the subsequent stress response have been linked to the development of inflammation and progression toward the more severe forms of the disease. Here, we demonstrate that DENV uses the NS2B3 protease complex to strategically target Nrf2 for degradation, leading to a progressive increase in oxidative stress, inflammation, and cell death in infected cells. This study underlines the pivotal role of the Nrf2 regulatory network in the context of DENV infection.

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