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 Pathogenic Roles of Macrophage Migration Inhibitory Factor during Dengue Virus Infection

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yung-Chun Chuang ◽  
Hong-Ru Chen ◽  
Trai-Ming Yeh
Keyword(s):  
Dengue Virus ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Immune Cell ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Knock Out

Dengue virus (DENV) infection is the most common cause of viral hemorrhagic fever, which can lead to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Hemorrhage and plasma leakage are two major hallmarks of DHF/DSS. Because the mechanisms causing these pathogenic changes are unclear, there is no effective therapy against DHF/DSS. In this review, we focus on the possible pathogenic effects of a pleiotropic cytokine, macrophage migration inhibitory factor (MIF), on the pathogenesis of DENV infection. MIF is a critical mediator of the host immune response and inflammation, and there is a correlation between the serum levels of MIF and disease severity in dengue patients. Furthermore, MIF knock-out mice exhibit less severe clinical disease and lethality. However, the role of MIF in the pathogenesis of DHF/DSS is not limited to immune cell recruitment. Recent evidence indicates that DENV infection induced MIF production and may contribute to vascular hyperpermeability and viral replication during DENV infection. The expression of both adhesion and coagulation molecules on MIF-stimulated monocytes and endothelial cells is also increased, which may contribute to inflammatory and anticoagulatory states during DHF/DSS. Therefore, blocking MIF production or its function may provide a solution for the treatment and prevention of DHF/DSS.

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 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 Melatonin Inhibits Dengue Virus Infection via the Sirtuin 1-Mediated Interferon Pathway

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 659
Author(s):  
Atthapan Morchang ◽  
Shilu Malakar ◽  
Kanchanaphan Poonudom ◽  
Sansanee Noisakran ◽  
Pa-thai Yenchitsomanus ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Production Cross ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Cell Types ◽  
Denv Infection ◽  
Sirtuin 1 ◽  
Natural Hormone ◽  
New Strategy ◽  
Post Entry

Dengue virus (DENV) is the causative pathogen in the life-threatening dengue hemorrhagic fever and dengue shock syndrome. DENV is transmitted to humans via the bite of an infected Aedes mosquito. Approximately 100 million people are infected annually worldwide, and most of those live in tropical and subtropical areas. There is still no effective drug or vaccine for treatment of DENV infection. In this study, we set forth to investigate the effect of melatonin, which is a natural hormone with multiple pharmacological functions, against DENV infection. Treatment with subtoxic doses of melatonin dose-dependently inhibited DENV production. Cross-protection across serotypes and various cell types was also observed. Time-of-addition assay suggested that melatonin exerts its influence during the post-entry step of viral infection. The antiviral activity of melatonin partly originates from activation of the sirtuin pathway since co-treatment with melatonin and the sirtuin 1 (SIRT1) inhibitor reversed the effect of melatonin treatment alone. Moreover, melatonin could modulate the transcription of antiviral genes that aid in suppression of DENV production. This antiviral mechanism of melatonin suggests a possible new strategy for treating DENV infection.

scholarly journals Type I interferons act directly on nociceptors to produce pain sensitization: Implications for viral infection-induced pain

2019 ◽  
Author(s):  
Paulino Barragan-Iglesias ◽  
Úrzula Franco-Enzástiga ◽  
Vivekanand Jeevakumar ◽  
Andi Wangzhou ◽  
Vinicio Granados-Soto ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Infections ◽  
Mrna Translation ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Drg Neurons ◽  
Pain Hypersensitivity ◽  
Type I Ifns ◽  
Pain Sensitization

ABSTRACTOne of the first signs of viral infection is body-wide aches and pain. While this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization are well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I interferons stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.SIGNIFICANCE STATEMENTIt is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. While specific mechanisms have been discovered for diverse bacteria and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type 1 interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling) that is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

scholarly journals UPDATE MANAGEMENT OF DENGUE COMPLICATION IN PEDIATRIC

2015 ◽  
Vol 2 (1) ◽  
pp. 1
Author(s):  
Soegeng Soegijanto
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Clinical Performance ◽  
Kidney Injury ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Liver Involvement ◽  
Dengue Virus Infection ◽  
Important Health ◽  
Grade Iii

Dengue virus infection is one of the important health problems in Indonesia, although the mortality rate has been decreased but many dengue shock syndrome cases is very difficult to be solving handled. It might be due to nature course of dengue virus infection is very difficult to predict of the earlier time of severity occur. THE AIM To get idea to make update management of dengue complication in pediatric. MATERIAL AND METHOD Data were compiled from Dr. Soetomo Hospital Surabaya in 2009. The diagnosis of all cases was based on criteria WHO 1997 and PCR examination in Institute Tropical Disease for identified serotype of dengue virus infection. The unusual cases of dengue virus infection were treated following the new WHO protocol in 2009. RESULT There were only 3 cases with serotype DEN 1, consisted 2 cases had age 1–4 years and 1 had age 5–14 years. 2 cases showed a severe clinical performance as dengue shock syndrome and 1 case showed as unusual case of dengue virus infection. Three report cases of: a. Dengue hemorrhagic fever grade III which liver involvement and had bilateral pleural effusion; b. Dengue hemorrhagic grade III with liver involvement and encephalopathy; c. Dengue hemorrhagic grade III with liver involvement acute kidney injury, myocardial involvement and encephalopathy. All the patients were treated according to new edition WHO protocol and all of the involving organ recovered along with the improvement of the disease. CONCLUSION Update management of dengue complication pediatric should be learned carefully used for helping unusual cases of dengue virus infection.

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.

scholarly journals Assessment of Prolonged Dengue Virus Infection in Dermal Fibroblasts and Hair-Follicle Dermal Papilla Cells

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 267
Author(s):  
Kai-Che Wei ◽  
Wan-Ju Wei ◽  
Yi-Shan Liu ◽  
Li-Chen Yen ◽  
Tsung-Hsien Chang
Keyword(s):  
Dengue Virus ◽  
Hair Follicle ◽  
Hair Loss ◽  
Human Hair ◽  
Dermal Papilla ◽  
Denv Infection ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Dermal Papilla Cells

Dengue virus (DENV)-mediated hair loss is one of the post-dengue fatigue syndromes and its pathophysiology remains unknown. Whether long-term or persistent infection with DENV in the scalp results in hair loss is unclear. In this study, we cultured human dermal fibroblasts (WS1 cells) and primary human hair-follicle dermal papilla cells (HFDPCs) in the long term with DENV-2 infection. The production of virion, the expression of inflammatory and anti-virus genes, and their signaling transduction activity in the infected cells were analyzed. DENV-2 NS3 protein and DENV-2 5′ UTR RNA were detected in fibroblasts and HFDPCs that were subjected to long-term infection with DENV-2 for 33 days. A significant amount of DENV-2 virion was produced by both WS1 cells and HFDPCs in the first two days of acute infection. The virion was also detected in WS1 cells that were infected in the long term, but HFDPCs failed to produce DENV-2 after long-term culture. Type I and type III interferons, and inflammatory cytokines were highly expressed in the acute phase of DENV infection in HFPDC and WS1 cells. However, in the long-term cultured cells, modest levels of anti-viral protein genes were expressed and we observed reduced signaling activity, which was correlated with the level of virus production changes. Long-term infection of DENV-2 downregulated the expression of hair growth regulatory factors, such as Rip1, Wnt1, and Wnt4. This in vitro study shows that the long-term infection with DENV-2 in dermal fibroblasts and dermal papilla cells may be involved with the prolonged-DENV-infection-mediated hair loss of post-dengue fatigue syndrome. However, direct evidence for viral replication in the human hair of a dengue victim or animal infection model is required.

scholarly journals Roles for Endothelial Cells in Dengue Virus Infection

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Nadine A. Dalrymple ◽  
Erich R. Mackow
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Capillary Permeability ◽  
Virus Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Dengue Virus Infection ◽  
Barrier Functions ◽  
Dengue Disease ◽  
Primary Fluid

Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The endothelium is the primary fluid barrier of the vasculature and ultimately the effects of dengue virus infection that cause capillary leakage impact endothelial cell (EC) barrier functions. The ability of dengue virus to infect the endothelium provides a direct means for dengue to alter capillary permeability, permit virus replication, and induce responses that recruit immune cells to the endothelium. Recent studies focused on dengue virus infection of primary ECs have demonstrated that ECs are efficiently infected, rapidly produce viral progeny, and elicit immune enhancing cytokine responses that may contribute to pathogenesis. Furthermore, infected ECs have also been implicated in enhancing viremia and immunopathogenesis within murine dengue disease models. Thus dengue-infected ECs have the potential to directly contribute to immune enhancement, capillary permeability, viremia, and immune targeting of the endothelium. These effects implicate responses of the infected endothelium in dengue pathogenesis and rationalize therapeutic targeting of the endothelium and EC responses as a means of reducing the severity of dengue virus disease.

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