Controlling Dengue Virus Infection Research Articles

Advances in the Epidemiology, Pathogenesis, Diagnostic Methods, and Vaccine Development of Dengue Fever: A Comprehensive Review.

Dengue fever (DF) is a common mosquito-borne viral infection caused by any of the four dengue virus (DENV) serotypes. In recent years, the global incidence of DF has risen rapidly, which has widely threatened the health of millions of people in the United States, Southeast Asia, and the Western Pacific. The challenges for the prevention and control of DENV infection have become increasingly severe. Over the years, advances in the area of DF research have been continuously updating. In this review, we provide an updated and more in-depth overview of dengue epidemiology and pathogenesis, along with recent progress in diagnostic approaches (including methods to address cross-reactivity with other flaviviruses) and an expanded discussion of current dengue vaccine development, such as CYD-TDV (Dengvaxia), TV003/TV005, and the new TAK-003. This comprehensive perspective aims to offer references for the prevention, clinical diagnosis, and control of the disease.

Domperidone inhibits dengue virus infection by targeting the viral envelope protein and nonstructural protein 1

Dengue is a mosquito-borne disease caused by dengue virus (DENV) infection, which remains a major public health concern worldwide owing to the lack of specific treatments or antiviral drugs available. This study investigated the potential repurposing of domperidone, an antiemetic and gastrokinetic agent, to control DENV infection. Domperidone was identified by pharmacophore-based virtual screening as a small molecule that can bind to both the viral envelope (E) and the nonstructural protein 1 (NS1) of DENV. Molecular dynamics (MD) simulations and surface plasmon resonance (SPR) analysis were subsequently performed to determine specific interactions of domperidone with the DENV E and NS1 proteins and their binding affinity. Treatment of immortalized human hepatocyte-like cells (imHC) with domperidone could inhibit DENV production and NS1 secretion in a dose-dependent manner following infection with DENV serotype 2. These inhibitory effects were mediated by reduction in viral RNA replication and viral E and NS1 protein expression, but not by interference with virus entry into cells or NS1 oligomerization. The suppression of DENV production and NS1 secretion by domperidone was observed across all four DENV serotypes to varying degrees between different virus strains. The findings from our study suggest viral target-based repurposing of domperidone for modulating DENV.

The Compound AT13148 Targeting AKT Suppresses Dengue Virus 2 Replication.

Background: Dengue virus (DENV) infection, caused by serotypes DENV 1-4, represents a significant global public health challenge, with no antiviral drugs currently available for treatment. The host Protein kinase B (AKT) signaling pathway is crucial for DENV infection, presenting a potential target for antiviral drug development. Objective: This study aimed to evaluate the antiviral activity of kinase inhibitors that target the AKT pathway, focusing on the compound AT13148. Methods: A mini-screening was conducted to identify kinase inhibitors with antiviral properties against DENV-2. The effects of AT13148 on viral RNA replication and translation were assessed in a dose- and time-dependent manner following DENV-2 entry. The mechanism of action was further investigated by evaluating the impact of AT13148 on AKT kinase activity and phosphorylation status. Results: AT13148 exhibited potent antiviral activity against DENV-2, significantly inhibiting viral RNA replication and translation post-entry. The compound was found to inhibit AKT kinase activity through hyperphosphorylation. Conclusion: The findings indicate that AT13148 effectively targets the AKT pathway, demonstrating potential as an antiviral therapeutic against DENV-2 by interfering with the virus's post-entry processes. Further in vivo studies are warranted to assess the efficacy of AT13148 in controlling DENV infection.

Allosteric inhibition of dengue virus RNA-dependent RNA polymerase by Litsea cubeba phytochemicals: a computational study

RNA-dependent RNA polymerase (RdRp) is considered a potential drug target for dengue virus (DENV) inhibition and has attracted attention in antiviral drug discovery. Here, we screened 121 natural compounds from Litsea cubeba against DENV RdRp using various approaches of computer-based drug discovery. Notably, we identified four potential compounds (Ushinsunine, Cassameridine, (+)-Epiexcelsin, (−)-Phanostenine) with good binding scores and allosteric interactions with the target protein. Moreover, molecular dynamics simulation studies were done to check the conformational stability of the complexes under given conditions. Additionally, we performed post-simulation analysis to find the stability of potential drugs in the target protein. The findings suggest Litsea cubeba-derived phytomolecules as a therapeutic solution to control DENV infection. Communicated by Ramaswamy H. Sarma

The cargo adapter protein CLINT1 is phosphorylated by the Numb-associated kinase BIKE and mediates dengue virus infection

The signaling pathways and cellular functions regulated by the four Numb-associated kinases are largely unknown. We reported that AAK1 and GAK control intracellular trafficking of RNA viruses and revealed a requirement for BIKE in early and late stages of dengue virus (DENV) infection. However, the downstream targets phosphorylated by BIKE have not yet been identified. Here, to identify BIKE substrates, we conducted a barcode fusion genetics-yeast two-hybrid screen and retrieved publicly available data generated via affinity-purification mass spectrometry. We subsequently validated 19 of 47 putative BIKE interactors using mammalian cell–based protein–protein interaction assays. We found that CLINT1, a cargo-specific adapter implicated in bidirectional Golgi-to-endosome trafficking, emerged as a predominant hit in both screens. Our experiments indicated that BIKE catalyzes phosphorylation of a threonine 294 CLINT1 residue both in vitro and in cell culture. Our findings revealed that CLINT1 phosphorylation mediates its binding to the DENV nonstructural 3 protein and subsequently promotes DENV assembly and egress. Additionally, using live-cell imaging we revealed that CLINT1 cotraffics with DENV particles and is involved in mediating BIKE’s role in DENV infection. Finally, our data suggest that additional cellular BIKE interactors implicated in the host immune and stress responses and the ubiquitin proteasome system might also be candidate phosphorylation substrates of BIKE. In conclusion, these findings reveal cellular substrates and pathways regulated by the understudied Numb-associated kinase enzyme BIKE, a mechanism for CLINT1 regulation, and control of DENV infection via BIKE signaling, with potential implications for cell biology, virology, and host-targeted antiviral design.

Whole inactivated dengue virus-loaded trimethyl chitosan nanoparticle-based vaccine: immunogenic properties in ex vivo and in vivo models

ABSTRACT Dengue virus (DENV) is a mosquito-borne virus that poses an incomparable public health problem, particularly in tropical and subtropical areas. Vaccination remains the most rational measure for controlling DENV infection. In this study, an ultraviolet irradiation (UV)-inactivated DENV-2 carried by N,N,N-trimethyl chitosan nanoparticles (UV-inactivated DENV2 TMC NPs) was investigated as a potential non-replicating dengue vaccine candidate. Using a human ex vivo model, the human monocyte-derived dendritic cells (MoDCs), we showed that TMC served as both a vaccine vehicle and a potent adjuvant. TMC NPs not only efficiently enhanced UV-inactivated DENV2 internalization into MoDCs but also greatly increased the breadth of UV-inactivated DENV2 immunogenicity to drive the maturation of MoDCs. Moreover, UV-inactivated DENV2 TMC NPs were highly immunogenic in mice, inducing greater levels of antibodies (total IgG, IgG1, IgG2a and neutralizing antibodies) and T cells (activated CD4⁺ and CD8⁺ T cells) against DENV-2 compared to soluble DENV-2 immunogens. Notably, the neutralizing activity of sera from mice immunized with UV-inactivated DENV2 TMC NPs was significantly augmented in the presence of complement activation, leading to the strong elimination of both DENV-2 particles and infected cells. We further showed that the immunogenicity of an inactivated dengue-based vaccine was significantly improved in a concentration-dependent manner. These positive results warrant further investigations of this platform of vaccine delivery for tetravalent vaccines or monovalent vaccines in sequential immunizations.

Major Histocompatibility Complex Class I Chain-Related A and B (MICA and MICB) Gene, Allele, and Haplotype Associations With Dengue Infections in Ethnic Thais.

Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness. MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (n = 166) and controls (n = 149). A replication cohort of patients with dengue (n = 222) was used to confirm specific MICB associations with disease. MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR], 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR, 0.41; 95% CI, .21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR, 0.43; 95% CI, .22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI, .14-.60). Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.

Anti-dengue Vaccines: From Development to Clinical Trials.

Dengue Virus (DENV) is an arbovirus (arthropod-borne virus). Four serotypes of DENV are responsible for the infectious disease called dengue that annually affects nearly 400 million people worldwide. Although there is only one vaccine formulation licensed for use in humans, there are other vaccine formulations under development that apply different strategies. In this review, we present information about anti-dengue vaccine formulations regarding development, pre-clinical tests, and clinical trials. The improvement in vaccine development against dengue is much needed, but it should be considered that the correlate of protection is still uncertain. Neutralizing antibodies have been proposed as a correlate of protection, but this ignores the key role of T-cell mediated immunity in controlling DENV infection. It is important to confirm the accurate correlate of protection against DENV infection, and also to have other anti-dengue vaccine formulations licensed for use.

Fog–Cloud Assisted IoT-Based Hierarchical Approach For Controlling Dengue Infection

Abstract The past five decades have witnessed the unprecedented contribution of arboviral diseases towards global morbidity and disability. It is primarily attributed due to unplanned urbanization, population explosion and globalization. Out of these, dengue is considered the most important arboviral disease because of its predominant growth in the past. The presented study explores the immense potential of Internet of things (IoT), fog and cloud computing for providing technology-based healthcare solutions for dengue virus (DENV) infection. In this paper, a hierarchical healthcare computing system for controlling DENV infection using fog–cloud-assisted IoT is proposed. This system provides a real-time remote diagnosis of DENV infection in individuals and monitors and predicts their health sensitivity during its infection period. The system uses fog computing to diagnose the DENV infection status of the individuals using $k$-means clustering and generates immediate diagnostic alerts to individuals, at the fog layer. Furthermore, the system uses cloud computing to monitor and predict the probabilistic health sensitivity of the DENV-infected individuals using Bayesian belief network and artificial neural network, respectively, at the cloud layer. The prediction of health sensitivity in the proposed system helps the infected individuals and healthcare agencies in determining the health vulnerability of DENV-infected individuals and preventing severe or permanent health losses in the future. The proposed system is experimentally evaluated using well-defined approaches, which conform to its validity and applicability. The results obtained from the experimental evaluations of the proposed system acknowledge the performance superiority and high efficiency of the system in delivering DENV-related healthcare services in real time.

Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Avocado (Persea americana) fruit extract (2R,4R)-1,2,4-trihydroxyheptadec-16-yne inhibits dengue virus replication via upregulation of NF-\u03baB\u2013dependent induction of antiviral interferon responses

Dengue virus (DENV) caused millions of infections around the world annually. Co-infection with different serotypes of DENV is associated with dengue hemorrhagic shock syndrome, leading to an estimate of 50% death rate. No approved therapies are currently available for the treatment of DENV infection. Hence, novel anti-DENV agents are urgently needed for medical therapy. Here we demonstrated that a natural product (2 R,4 R)-1,2,4-trihydroxyheptadec-16-yne (THHY), extracted from avocado (Persea americana) fruit, can inhibit DENV-2 replication in a concentration-dependent manner and efficiently suppresses replication of all DENV serotypes (1–4). We further reveal that the NF-κB-mediated interferon antiviral response contributes to the inhibitory effect of THHY on DENV replication. Using a DENV-infected ICR suckling mouse model, we found that THHY treatment caused an increased survival rate among mice infected with DENV. Collectively, these findings support THHY as a potential agent to control DENV infection.

Improvement of the Dengue Virus (DENV) Nonhuman Primate Model via a Reverse Translational Approach Based on Dengue Vaccine Clinical Efficacy Data against DENV-2 and -4.

ABSTRACTRecent data obtained with the live-attenuated tetravalent dengue CYD-TDV vaccine showed higher protective efficacy against dengue virus type 4 (DENV-4) than against DENV-2. In contrast, results from previous studies in nonhuman primates predicted comparable high levels of protection against each serotype. Maximum viral loads achieved in macaques by subcutaneous inoculation of DENV are generally much lower than those observed in naturally dengue virus-infected humans. This may contribute to an overestimation of vaccine efficacy. Using more-stringent DENV infection conditions consisting of the intravenous inoculation of 107 50% cell culture infectious doses (CCID50) in CYD-TDV-vaccinated macaques, complete protection (i.e., undetectable viral RNA) was achieved in all 6 monkeys challenged with DENV-4 and in 6/18 of those challenged with DENV-2, including transiently positive animals. All other infected macaques (12/18) developed sustained DENV-2 RNAemia (defined as detection of viral RNA in serum samples) although 1 to 3 log10 units below the levels achieved in control animals. Similar results were obtained with macaques immunized with either CYD-TDV or monovalent (MV) CYD-2. This suggests that partial protection against DENV-2 was mediated mainly by CYD-2 and not by the other CYDs. Postchallenge induction of strong anamnestic responses, suggesting efficient vaccine priming, likely contributed to the reduction of DENV-2 RNAemia. Finally, an inverse correlation between DENV RNA titers postchallenge and vaccine-induced homotypic neutralizing antibody titers prechallenge was found, emphasizing the key role of these antibodies in controlling DENV infection. Collectively, these data show better agreement with reported data on CYD-TDV clinical vaccine efficacy against DENV-2 and DENV-4. Despite inherent limitations of the nonhuman primate model, these results reinforce its value in assessing the efficacy of dengue vaccines.IMPORTANCE The nonhuman primate (NHP) model is the most widely recognized tool for assessing the protective activity of dengue vaccine candidates, based on the prevention of postinfection DENV viremia. However, its use has been questioned after the recent CYD vaccine phase III trials, in which moderate protective efficacy against DENV-2 was reported, despite full protection against DENV-2 viremia previously being demonstrated in CYD-vaccinated monkeys. Using a reverse translational approach, we show here that the NHP model can be improved to achieve DENV-2 protection levels that show better agreement with clinical efficacy. With this new model, we demonstrate that the injection of the CYD-2 component of the vaccine, in either a monovalent or a tetravalent formulation, is able to reduce DENV-2 viremia in all immunized animals, and we provide clear statistical evidence that DENV-2-neutralizing antibodies are able to reduce viremia in a dose-dependent manner.

In silico design of a Zika virus non-structural protein 5 aiming vaccine protection against zika and dengue in different human populations

BackgroundThe arboviruses Zika virus (ZIKV) and Dengue virus (DENV) have important epidemiological impact in Brazil and other tropical regions of the world. Recently, it was shown that previous humoral immunity to DENV enhances ZIKV replication in vitro, which may lead to more severe forms of the disease. Thus, traditional approaches of vaccine development aiming to control viral infection through neutralizing antibodies may induce cross-reactive enhancing antibodies. In contrast, cellular immune response was shown to be capable of controlling DENV infection independently of antibodies. The aim of the present study was to design a flavivirus NS5 protein capable of inducing a cellular immune response against DENV and ZIKV.MethodsA consensus sequence of ZIKV NS5 protein was designed among isolates from various continents. Epitopes were predicted for the most prevalent alleles of class I and II HLA in the Brazilian population. Then, this epitopes were analyzed with regard to their conservation, population coverage and distribution along the whole antigen.ResultsNineteen epitopes predicted to be more reactive (percentile rank <1) and 100% conserved among ZIKV and DENV serotypes were selected. The distribution of such epitopes along the protein was shown on a three-dimensional model and population coverage was calculated for different regions of the world. The designed protein was predicted to be stable and the distribution of selected epitopes was shown to be homogeneous along domains. The population coverage of selected epitopes was higher than 50% for most of tropical areas of the world.ConclusionSuch results indicate that the proposed antigen has the potential to induce protective cellular immune response to ZIKV and DENV in different human populations of the world.

Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents.

Viral hijacking and manipulation of host-cell biosynthetic pathways by human enveloped viruses are shared molecular events essential for the viral lifecycle. For Flaviviridae members such as hepatitis C virus and dengue virus (DENV), one of the key subsets of cellular pathways that undergo manipulation is the lipid metabolic pathways, underlining the importance of cellular lipids and, in particular, lipid droplets (LDs) in viral infection. Here, we hypothesize that targeting cellular enzymes that act as key regulators of lipid homeostasis and LD formation could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with all DENV serotypes (1–4) circulating around the world. Using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrate that inhibition of SKI-1/S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the LD numbers and LD-positive areas and provides a means of effectively inhibiting infection by DENV (1–4). Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV infection [median inhibitory dose (EC50) = 1.2 microM; median cytotoxic dose (CC50) = 81 microM; selectivity index (SI) = 68)] and a ~3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid, which acts as an inducer of LD formation in PF-429242-treated and non-treated control cells. Collectively, our results demonstrate that human SKI-1/S1P is a potential target for indirect-acting pan-serotypic anti-DENV agents and reveal new therapeutic opportunities associated with the use of lipid-modulating drugs for controlling DENV infection.

Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication.

Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and disease outcome. Although the interferon (IFN) response, which is central to host protective immunity, has been reported to limit DENV replication, the molecular details of how DENV infection is modulated by IFN treatment are elusive. In this study, by employing a gain-of-function screen using a type I IFN-treated cell-derived cDNA library, we identified a previously uncharacterized gene, C19orf66, as an IFN-stimulated gene (ISG) that inhibits DENV replication, which we named Repressor of yield of DENV (RyDEN). Overexpression and gene knockdown experiments revealed that expression of RyDEN confers resistance to all serotypes of DENV in human cells. RyDEN expression also limited the replication of hepatitis C virus, Kunjin virus, Chikungunya virus, herpes simplex virus type 1, and human adenovirus. Importantly, RyDEN was considered to be a crucial effector molecule in the IFN-mediated anti-DENV response. When affinity purification-mass spectrometry analysis was performed, RyDEN was revealed to form a complex with cellular mRNA-binding proteins, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif-related protein 1 (LARP1). Interestingly, PABPC1 and LARP1 were found to be positive modulators of DENV replication. Since RyDEN influenced intracellular events on DENV replication and, suppression of protein synthesis from DENV-based reporter construct RNA was also observed in RyDEN-expressing cells, our data suggest that RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells.

New insights into the immunopathology and control of dengue virus infection.

Dengue virus poses a major threat to global public health: two-thirds of the world's population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus.

Dengue Virus Infection of Aedes aegypti Requires a Putative Cysteine Rich Venom Protein.

Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease and mortality worldwide. There is no specific antiviral therapy or vaccine for DENV infection. Alterations in gene expression during DENV infection of the mosquito and the impact of these changes on virus infection are important events to investigate in hopes of creating new treatments and vaccines. We previously identified 203 genes that were ≥5-fold differentially upregulated during flavivirus infection of the mosquito. Here, we examined the impact of silencing 100 of the most highly upregulated gene targets on DENV infection in its mosquito vector. We identified 20 genes that reduced DENV infection by at least 60% when silenced. We focused on one gene, a putative cysteine rich venom protein (SeqID AAEL000379; CRVP379), whose silencing significantly reduced DENV infection in Aedes aegypti cells. Here, we examine the requirement for CRVP379 during DENV infection of the mosquito and investigate the mechanisms surrounding this phenomenon. We also show that blocking CRVP379 protein with either RNAi or specific antisera inhibits DENV infection in Aedes aegypti. This work identifies a novel mosquito gene target for controlling DENV infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses.

Suppressed expression of miR-378 targeting gzmb in NK cells is required to control dengue virus infection.

Dengue virus (DENV) remains a major public health threat because no vaccine or drugs are available for the prevention and treatment of DENV infection, and the immunopathogenesis mechanisms of DENV infection are not fully understood. Cytotoxic molecules, such as granzyme B (GrzB), may be necessary to control viral infections. However, the exact role of GrzB during DENV infection and the mechanisms regulating GrzB expression during DENV infection are not clear. This study found that miR-27a*, miR-30e, and miR-378 were down-regulated in DENV-infected patients, and DENV infection in humans induced a significant up-regulation of GrzB in natural killer (NK) cells and CD8+ T cells. Further investigation indicated that NK cells, but not CD8+ T cells, were the major sources of GrzB, and miR-378, but not miR-27a* or miR-30e, suppressed GrzB expression in NK cells. Notably, we found that overexpression of miR-378 using a miR-378 agomir in DENV-infected mice inhibited GrzB expression and promoted DENV replication. These results suggest the critical importance of miR-378 in the regulation of GrzB expression and a protective role for GrzB in controlling DENV replication in vivo. Therefore, this study provides a new insight into the immunopathogenesis mechanism of DENV infection and a biological basis for the development of new therapeutic strategies to control DENV infection.

Innate Antiviral Immunity against Dengue Virus

Dengue virus (DENV), the most prevalent mosquito-borne viral diseases in humans worldwide, causes dengue fever, a mild form of the disease, as well as dengue hemorrhagic fever/dengue shock syndrome, a more severe form which can be life-threatening. The four serotypes of DENV (DENV1-4) are positive-sense, single stranded RNA virus belonging to the Flaviviridae family and are transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Together, they are estimated to cause almost 100 million symptomatic cases, 2.1 million cases of dengue hemorrhagic fever/dengue shock syndrome, and 21,000 deaths per year worldwide. There are currently no effective vaccines or antiviral treatment for DENV. Innate immune defenses play a key role in controlling DENV infection in the early stages. Herein we review the innate antiviral immunity against DENV by delineating the intracellular mechanisms of the immune response and the evasion mechanisms evolved by the virus. A better understanding of the innate immune response will impact the development of novel animal models, antiviral drugs as well as potential targeted adjuvants for DENV vaccines.

Vitamin D role in Dengue virus replication and the inflammatory response in human macrophages.

Vitamin D role in Dengue virus replication and the inflammatory response in human macrophages.