Dengue Virus Research Articles

Fc-FcγR interactions during infections: From neutralizing antibodies to antibody-dependent enhancement.

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fcγ receptors (FcγRs) on effector leukocytes. Fc-FcγR interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific FcγR pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease.

The ApoA1-mimetic peptide 4F blocks flavivirus NS1-triggered endothelial dysfunction and protects against lethal dengue virus challenge

Flavivirus infections result in a variety of outcomes, from clinically inapparent infections to severe, sometimes fatal cases characterized by hemorrhagic manifestations and vascular leakage leading to shock (dengue), meningomyeloencephalitis (West Nile), and congenital abnormalities (Zika). Although there are approved vaccines against several flaviviruses, potentially enhancing cross-reactive immune responses have complicated the development and implementation of vaccines against dengue and Zika viruses, and no specific therapeutics currently exist. The flavivirus nonstructural protein 1 (NS1) is a promising antiviral target because it is a conserved multifunctional virulence factor that directly triggers vascular leak. We previously showed that interactions between NS1 and the ApoA1 lipoprotein modulate DENV infection. Here, we evaluated the potential of the ApoA1-mimetic peptide, 4F, to interfere with endothelial dysfunction mediated by the NS1 protein of dengue, Zika, and West Nile flaviviruses. In an in vitro model consisting of human endothelial cell monolayers, 4F inhibited NS1-induced hyperpermeability, as measured by a transendothelial electrical resistance assay, and prevented NS1-triggered disruption of the endothelial glycocalyx layer. We also demonstrate that treatment with 4F inhibited NS1 interaction with endothelial cells. Finally, we show that 4F protects against lethal DENV challenge in a mouse model, reducing morbidity and mortality in a dose-dependent manner. Our data demonstrate the potential of 4F to inhibit flavivirus NS1-mediated pathology and severe dengue disease in mice and suggest that 4F can also serve as a molecular tool to probe different NS1 functions in vitro and in vivo.

Circulating dengue virus serotypes, demographics, and epidemiology in the 2023 dengue outbreak in Chittagong, Bangladesh.

Dengue is a serious epidemic for Bangladesh affecting thousands of lives. This study aimed to identify and determine the prevalence of the circulating variants of dengue virus (DENV) and their association with demographics and clinical manifestations among the dengue-infected patients. A total of 711 participants with NS1 antigen positivity were enrolled, followed by viral RNA extraction from the collected blood samples and a multiplex real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to determine the dengue virus serotypes. Of 711 dengue-infected patients, 503 (70.7%) were male. Among different age groups, most of the patients were 21-30 years old (n = 255, 35.9%). The DENV2 (n = 483, 67.9%) serotype was more prevalent than the DENV3 (n = 144, 20.3%) and DENV1 (n = 84, 11.8%). The duration of fever was highest in the DENV-1 patients (4.79 ± 1.84 days) in contrast to DENV-3 (4.48 ± 1.68 days) and DENV-2 (4.33 ± 1.45 days) (P = 0.039). Importantly, five highly populated areas were identified as dengue hotspots in Chittagong metropolitan city. Our results provide crucial insights into the patterns of dengue virus transmission and severity among southern Bangladeshi population, thereby aiding in the development of targeted public health interventions and management strategies to combat future outbreaks.

A mini review of antiviral compounds against dengue virus

A mini review of antiviral compounds against dengue virus

Quantification of the interaction forces between dengue virus and dopamine type-2 receptor using optical tweezers

BackgroundDengue virus (DENV) causes the most significant mosquito-borne viral disease with a wide spectrum of clinical manifestation, including neurological symptoms associated with lethal dengue diseases. Dopamine receptors are expressed in central nervous system, and dopamine antagonists have been reported to exhibit antiviral activity against DENV infection in vivo and in vitro. Although identification of host-cell receptor is critical to understand dengue neuropathogenesis and neurotropism, the involvement of dopamine receptors in DENV infection remains unclear.ResultsWe exploited the sensitivity and precision of force spectroscopy to address whether dopamine type-2 receptors (D2R) directly interact with DENV particles at the first step of infection. Using optical tweezers, we quantified and characterized DENV binding to D2R expressed on Chinese hamster ovary (CHO) cells. Our finding suggested that the binding was D2R- and DENV-dependent, and that the binding force was in the range of 50–60 pN. We showed that dopamine antagonists prochlorperazine (PCZ) and trifluoperazine (TFP), previously reported to inhibit dengue infection, interrupt the DENV-D2R specific binding.ConclusionsThis study demonstrates that D2R could specifically recognize DENV particles and function as an attachment factor on cell surfaces for DENV. We propose D2R as a host receptor for DENV and as a potential therapeutic target for anti-DENV drugs.Graphical abstract

Evaluating Antibiotic Misuse and Cost Analysis Among Hospitalized Dengue Virus-Infected Adults: Insights From a Retrospective Cohort Study.

Dengue is a prevalent cause of acute febrile illness, predominantly in Asia, where it necessitates supportive care without the need for antibiotics. This study aimed to evaluate antibiotic usage and analyze hospitalization costs among adults infected with the dengue virus. This retrospective cohort study was conducted at the Hospital for Tropical Diseases, Thailand, in 2022. Two independent reviewers assessed all adult cases with confirmed dengue from 2016 to 2021. Determinants of inappropriateness were analyzed using Poisson regression. The study included 249 participants with over half presenting with severe dengue or dengue with warning signs upon admission. The cumulative incidence of antibiotic use was 9.3% (95% CI, 8.23-10.47), predominantly involving empirical treatment strategies. Ceftriaxone and doxycycline were the most frequently prescribed antibiotics. Notably, patients who received empirical antibiotics showed no definite or presumed bacterial infections. Among those who received definite strategies, inappropriate durations, including both short treatments and the overuse of broad-spectrum antibiotics, were observed. A private ward admission was identified as a significant predictor of inappropriate use, with an incidence rate ratio of 4.15 (95% CI, 1.16-14.82) compared with intensive care unit admission. Direct medical costs did not differ significantly between appropriate and inappropriate uses. The incidence of antibiotic use among dengue cases was moderate; however, inappropriate use by indication was observed. Antimicrobial stewardship strategies should be encouraged, particularly in patients with dengue with warning signs admitted to a general or private ward. Direct medical costs between appropriate and inappropriate use were comparable.

Homology Modeling and Expression of Recombinant NS5-RdRp Based on the Indonesian Local Strain of Dengue Virus for Anti-Dengue Drug Development

This study aims to isolate the RNA-dependent RNA polymerase (RdRp) gene of the dengue virus (DENV) isolates from Indonesia, determine the serotype of the local DENV strain through homology modeling, and express the recombinant RdRp protein in Escherichia coli BL21 (DE3), as the target for anti-dengue drug development. We utilize reverse transcription- polymerase chain reaction (RT-PCR) and nested PCR for serotyping the DENV isolates, obtained from Hasan Sadikin Hospital, Indonesia. Then, followed by the extraction and purification of the RdRp amplicon for gene sequencing. The resulting RdRp gene sequences are translated into amino acid sequences, which are then used for protein modeling and the construction of a recombinant plasmid for RdRp protein expression. As the result, the RdRp gene, which belongs to the non-structural protein 5 (NS5) of DENV, was successfully isolated and sequenced from DENV RNA samples. Based on serotyping results and homology modeling, the serotype of the isolate DENV was identified as serotype-3. The isolated NS5-RdRp gene from the local strain was then inserted into the pET28a(+) plasmid and transformed into E. coli BL21(DE3) as the host cell. Recombinant NS5-RdRp was predominantly found in the insoluble fraction with a molecular weight of 72 kDa. Future studies on the development of an anti-dengue drug model that confirms the inhibition of the binding domain in the recombinant RdRp protein structure will be required to provide more insight and expand the development of a universal anti-dengue strategy in Indonesia.

Larval crowding enhances dengue virus loads in Aedes aegypti, a relationship that might increase transmission in urban environments.

Climate change and urbanization will alter the global distribution of disease vectors, changing the disease burden in yet unpredictable ways. Aedes aegypti is a mosquito responsible for transmitting dengue, Zika, chikungunya, and yellow fever viruses that breeds in containers associated with urban environments. We sought to understand how ambient temperature and larval densities in the immature aquatic phases determine adult life history traits and dengue virus loads post-infection. We predicted that larval crowding and high temperatures would both lead to smaller mosquitoes that might struggle to invest in an immune response and, hence, would exhibit high viral loads. We first examined larval densities from urban and rural areas via a meta-analysis. We then used these data to inform a laboratory-based 2x2 design examining the interacting effects of temperature (21 vs. 26°C) and density (0.2 vs. 0.4 larvae/mL) on adult life history and dengue virus loads. We found that urban areas had an ~8-fold increase in larval densities compared to more rural sites. In the lab, we found that crowding had more impact on mosquito traits than temperature. Crowding led to slower development, smaller mosquitoes, less survival, lower fecundity, and higher viral loads, as predicted. The higher temperature led to faster development, reduced fecundity, and lower viral loads. The virus-reducing effect of higher temperature rearing was, however, overwhelmed by the impact of larval crowding when both factors were present. These data reveal complex interactions between the environmental effects experienced by immature mosquitoes and adult traits. They especially highlight the importance of crowding with respect to adult viral loads. Together, these data suggest that urban environments might enhance dengue virus loads and, therefore, possibly transmission, a concerning result given the increasing rates of urbanization globally.

Reconciling heterogeneous dengue virus infection risk estimates from different study designs.

Uncovering rates at which susceptible individuals become infected with a pathogen, i.e. the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology are considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, have not been assessed. Using 26 years of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence was 2.46 to 4.33-times higher than case-derived FOI. Correlation between seroprevalence-derived and case-derived FOI was moderate (correlation coefficient=0.46) and no systematic bias. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.

Synergistic Role of the AuAg-Fe3O4 Nanoenzyme for Ultrasensitive Immunoassay of Dengue Virus.

A combination of magnetic and noble metal nanoparticles (NPs) has recently emerged as a potential substance for rapid and sensitive immunosorbent assays. However, to make the assay an alternative method for Enzyme-linked immunosorbent assay, the individual role of each nanoparticle must be explored properly. In this work, an immunoassay has been proposed using two antibody-conjugated iron oxide nanoparticles (Fe3O4NPs) and gold-silver bimetallic nanoparticles (AuAgNPs) to enhance the sensitivity of virus detection by colorimetric TMB/H2O2 signal amplification. A synergistic effect is monitored between Fe3O4NPs and AuAgNPs, which is explored for colorimetric virus detection. The sensor exploits the synergistic effect between the nanoparticles to successfully detect a wide range of dengue virus-like particle (DENV-LP) concentrations ranging from 10 to 100 pg/mL with a detection limit of up to 2.6 fg/mL. In the presence of a target DENV-LP, a sandwich-like structure is formed, which restricts the electron transfer and the associated synergistic effect between the nanoparticles, restricting the TMB oxidation process. Therefore, the synergistic effect is the key to the present work, which accounts for the enhanced rate of the enzymatic reaction on TMB and makes the current method of virus detection more sensitive and reliable compared to the others.

Development of a competition assay to assess the in vitro fitness of dengue virus serotypes using an optimized serotype-specific qRT-PCR.

Comparing the in vitro fitness of dengue virus (DENV) isolates is a pivotal approach to assess the contribution of DENV strains' replicative fitness to epidemiological contexts, including serotype replacements. Competition assays are the gold standard to compare the in vitro replicative fitness of viral strains. Implementing competition assays between DENV serotypes requires an experimental setup and an appropriate read-out to quantify the viral progeny of strains belonging to different serotypes. In the current study, we optimized an existing serotyping qRT-PCR by adapting primer/probe design and multiplexing the serotype-specific qRT-PCR reactions, allowing to accurately detect and quantify all four DENV serotypes. The qRT-PCR was specific, had a limit of detection of at least 5.08×101, 5.16×101, 7.14×101 and 1.36 ×101 genome copies/μL, an efficiency of 1.993, 1.975, 1.902, 1.898 and a linearity (R2) of 0.99975, 0.99975, 0.9985, 0.99965 for DENV-1, -2, -3 and -4 respectively. Challenge of this multiplex serotype-specific qRT-PCR on mixes of viral supernatants containing known concentrations of strains from two serotypes evidenced an accurate quantification of the amount of genome copies of each serotype. We next developed an in vitro assay to compare the replicative fitness of two DENV serotypes in the human hepatic cell line HuH7: quantification of the viral progeny of each serotype in the inoculum and the supernatant using the serotype-specific multiplex qRT-PCR unveiled an enrichment of the supernatant in DENV-1 genome copies, uncovering the enhanced replicative fitness of this DENV-1 isolate. This optimized qRT-PCR combined to a relevant cellular model allowed to accurately quantify the viral progeny of two DENV strains belonging to two different serotypes in a competition assay, allowing to determine which strain had a replicative advantage. This reliable experimental setup is adaptable to the comparative study of the replicative fitness of any DENV serotypes.

The Effect of a Combination of Ethanol Extract from Leaves and Flowers of Plumeria acuminate L. Against Aedes aegypti Larvae

Aedes aegypti is the primary vector that causes dengue virus (DENV) infection. Ae. aegypti resistance to abate (Temephos) has occurred in Indonesia and several other countries. Innovations are needed to develop alternative ingredients that can be used as natural larvacides. The Plumeria acuminate L. is an Indonesian plant with metabolites that have the potential to act as larvicides. This study aims to determine the potential combination of ethanol extract of P. acuminate L. leaves and flowers as a larvicide for A. aegypti. A laboratory experimental study with a post-test-only control group design was carried out on Ae. aegypti larvae instar III. The larvicide test was carried out according to WHO standards in 2005 with concentrations of 10000, 7500, 5000, and 2500 ppm, as well as control (water and 1% DMSO), with 20 larvae for each concentration. The observation was carried out at the 24th and 48th hours with 3 repetitions. Larval mortality data was analyzed using one-way ANOVA statistical tests to determine significant differences and lethal concentrations (LC50 and LC90) were calculated using probit analysis using SPSS software. The mortality of Ae. aegypti larvae due to the administration of a combined ethanolic extract of P. acuminate L. leaves and flowers was the highest at doses of 10000 and 7500 ppm, which was 100% with lethal concentrations of LC50 and LC90 of 3364.715 and 6293.759 ppm at the 24th hour observation, whereas at the 48th-hour observation, lethal concentrations were detected at 1767.998 and 2941.138 ppm, respectively. One-way ANOVA analysis test showed a significant difference in Ae. aegypti larval mortality due to the administration of a combined ethanol extract of P. acuminate L. leaves and flowers at 24th-hour observation (p = 0.000) and (p = 0.013) at 48th hour observation. The combination of ethanol extract of P. acuminate L. leaves and flowers showed larvicidal activity against Ae. aegypti larvae as evidenced by larvae mortality which were influenced by concentration and observation time.

Molecular epidemiology and evolutionary characteristics of dengue virus 2 in East Africa

Despite the increasing burden of dengue, the regional emergence of the virus in Kenya has not been examined. This study investigates the genetic structure and regional spread of dengue virus-2 in Kenya. Viral RNA from acutely ill patients in Kenya was enriched and sequenced. Six new dengue-2 genomes were combined with 349 publicly available genomes and phylogenies used to infer gene flow between Kenya and other countries. Analyses indicate two dengue-2 Cosmopolitan genotype lineages circulating in Kenya, linked to recent outbreaks in coastal Kenya and Burkina Faso. Lineages circulating in Western, Southern, and Eastern Africa exhibiting similar evolutionary features are also reported. Phylogeography suggests importation of dengue-2 into Kenya from East and Southeast Asia and bidirectional geneflow. Additional lineages circulating in Africa are also imported from East and Southeast Asia. These findings underscore how intermittent importations from East and Southeast Asia drive dengue-2 circulation in Kenya and Africa more broadly.

PREVENTIVE BEHAVIORS FOR DENGUE HEMORRHAGIC FEVER

Dengue fever is a viral infection caused by the dengue virus which is transmitted to humans through the bite of an infected mosquito. About half of the world's population is now at risk of dengue fever with an estimated 100–400 million infections occurring annually. This study aims to determine factors related to dengue prevention behavior in the East Ogan Komering Ulu District Health Service in 2024. The design of this research is quantitative with a cross-sectional approach. The population of this study was visits to the Gumawang Health Center in 2024. The sample in this study consisted of 93 respondents. The sampling method used purposive sampling. This research was carried out on 15-26 February 2024. Data was collected using a questionnaire. Bivariate data analysis used the Chi-Square test and multivariate logistic regression. Data collection using questionnaires. Results of statistical test analysis using the Chi-Square statistical test. The results of the study knowledge (p value 0.022), draining the landfill (p value 0.047), preventive measures (p value 0.005) and ventilation (p value (0.017). Age (p value 0.35), mosquito wire installation (p value 0.47) with dengue hemorrhagic fever (DHF) prevention behaviour at the East Ogan Komering Ulu District Health Office in 2024. The most dominant factor with dengue hemorrhagic fever (DHF) prevention behaviour is DHF prevention measures (p Value = 0.003) (OR 0.252). Conclusion There is a relationship between knowledge, landfill draining, preventive measures and ventilation. For the Health Office to carry out dengue prevention activities, carried out routinely and scheduled integrated in basic health services.

Inhibition of sterol O-acyltransferase 1 blocks Zika virus infection in cell lines and cerebral organoids

Viruses depend on host metabolic pathways and flaviviruses are specifically linked to lipid metabolism. During dengue virus infection lipid droplets are degraded to fuel replication and Zika virus (ZIKV) infection depends on triglyceride biosynthesis. Here, we systematically investigated the neutral lipid–synthesizing enzymes diacylglycerol O-acyltransferases (DGAT) and the sterol O-acyltransferase (SOAT) 1 in orthoflavivirus infection. Downregulation of DGAT1 and SOAT1 compromises ZIKV infection in hepatoma cells but only SOAT1 and not DGAT inhibitor treatment reduces ZIKV infection. DGAT1 interacts with the ZIKV capsid protein, indicating that protein interaction might be required for ZIKV replication. Importantly, inhibition of SOAT1 severely impairs ZIKV infection in neural cell culture models and cerebral organoids. SOAT1 inhibitor treatment decreases extracellular viral RNA and E protein level and lowers the specific infectivity of virions, indicating that ZIKV morphogenesis is compromised, likely due to accumulation of free cholesterol. Our findings provide insights into the importance of cholesterol and cholesterol ester balance for efficient ZIKV replication and implicate SOAT1 as an antiviral target.

Sulfoglycodendron Antivirals with Scalable Architectures and Activities.

Many viruses initiate their cell-entry by binding their multisubunit receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglycodendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multiprotein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed the detailed nature of binding between these antivirals and viral protein receptors and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

Identification and functional analysis of C-type lectin from mosquito Aedes albopictus in response to dengue virus infection

BackgroundC-type lectins (CTLs) are a large family of proteins with sugar-binding activity. CTLs contain an evolutionarily conserved C-type lectin domain (CTLD) that binds microbial carbohydrates in a calcium-dependent manner, thereby playing a key role in both microbial pathogenesis and innate immune responses. Aedes albopictus is an important vector for transmitting dengue virus (DENV) worldwide. Currently, the molecular characteristics and functions of CTLs in Ae. albopictus are largely unknown.MethodsTranscripts encoding CTL proteins in the Ae. albopictus genome assembly were analyzed via sequence blast. Phylogenetic analysis and molecular characterization were performed to identify the functional domains of the CTLs. Quantitative analysis was performed to determine the gene expression features of CTLs during mosquito development and in different tissues of female adults after blood feeding. In addition, the functional role of CTLs in response to DENV infection was investigated in Ae. albopictus mosquito cells.ResultsWe identified 39 transcripts encoding CTL proteins in the Ae. albopictus transcriptome. Aedes albopictus CTLs are classified into three groups based on the number of CTLDs and the domain architecture. These included 29 CTL-Ss (single-CTLDs), 1 immulectins (dual-CTLD) and 9 CTL-Xs (CTLDs with other domains). Phylogenetic analysis and structural modeling indicated that CTLs in Ae. albopictus are highly conserved with the homologous CTLs in Aedes aegypti. The expression profile assay revealed differential expression patterns of CTLs in both developmental stages and in adult female tissues. Knockdown and overexpression of three CTLs (CTL-S12, S17 and S19) confirmed that they can promote dengue virus infection in Ae. albopictus cells.ConclusionsThe CTL genes in Ae. albopictus mosquito and other mosquito species are evolutionarily conserved and exhibit different developmental and tissue expression features. The functional assay indicated that three CTLs in Ae. albopictus mosquitoes are involved in promoting dengue virus infection. Our study revealed that CTLs play important roles in both the physiological processes and viral infection in mosquito vectors.Graphical

Machine learning, network pharmacology, and molecular dynamics reveal potent cyclopeptide inhibitors against dengue virus proteins.

The dengue virus is a major global health hazard responsible for an estimated 390 million diseases yearly. This study focused on identifying cyclopeptide inhibitors for envelope structural proteins E, NS1, NS3, and NS5. Additionally, 5579 cyclopeptides were individually screened against the four target proteins using a machine learning-based quantitative structure-activity relationship model. Subsequently, the best 10 cyclopeptides from each protein were selected for molecular docking with their corresponding proteins. Moreover, the protein-peptide complexes with the highest affinity were subjected to a 100-ns molecular dynamics simulation. The protein-protein complexes exhibited superior structural stability and binding interactions. Based on the results of the MD simulation analyses, which included checking values for Root Mean Square Deviation, Root Mean Square Fluctuation, Principal Component Analysis (PCA), free energy landscapes, and energetic components, it was found that NS5-CP03714 complex is more stable and has stronger binding interactions than NS3-CP02054. PCA and free energy landscape plots have confirmed the higher conformational stability of NS5-CP03714. Analysis of the energetic components revealed that NS5-CP03714 (total binding energy = -47.19kcal/mol) exhibits more favorable interaction energies and overall binding energy compared to NS3-CP02054 (total binding energy = -27.36kcal/mol), suggesting a stronger and more stable formation of the complex. In addition, the drug-target network of two specific peptides (CP02950 and CP05582) and their associated target proteins were analyzed. This analysis revealed valuable information about their ability to target several proteins and their potential for broad-spectrum activity. Additional experimental investigations are necessary to validate these computational results and assess the efficacy of identified peptide inhibitors in biological systems.

Dengue NS1 interaction with lipids alters its pathogenic effects on monocyte derived macrophages

BackgroundWhile dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity.MethodsPrimary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1β levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF.ResultsSignificantly higher levels of IL-1β were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1β when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF.ConclusionsAs RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions.

Trends and insights in dengue virus research globally: a bibliometric analysis (1995–2023)

BackgroundDengue virus (DENV) is the most widespread arbovirus. The World Health Organization (WHO) declared dengue one of the top 10 global health threats in 2019. However, it has been underrepresented in bibliometric analyses. This study employs bibliometric analysis to identify research hotspots and trends, offering a comprehensive overview of the current research dynamics in this field.ResultsWe present a report spanning from 1995 to 2023 that provides a unique longitudinal analysis of Dengue virus (DENV) research, revealing significant trends and shifts not extensively covered in previous literature. A total of 10,767 DENV-related documents were considered, with a notable increase in publications, peaking at 747 articles in 2021. Plos Neglected Tropical Diseases has become the leading journal in Dengue virus research, publishing 791 articles in this field—the highest number recorded. Our bibliometric analysis provides a comprehensive mapping of DENV research across multiple dimensions, including vector ecology, virology, and emerging therapies. The study delineates a complex network of immune response genes, including IFNA1, DDX58, IFNB1, STAT1, IRF3, and NFKB1, highlighting significant trends and emerging themes, particularly the impacts of climate change and new outbreaks on disease transmission. Our findings detail the progress and current status of key vaccine candidates, including the licensed Dengvaxia, newer vaccines such as Qdenga and TV003, and updated clinical trials. The study underscores significant advancements in antiviral therapies and vector control strategies for dengue, highlighting innovative drug candidates such as AT-752 and JNJ-1802, and the potential of drug repurposing with agents like Ribavirin, Remdesivir, and Lopinavir. Additionally, it discusses biological control methods, including the introduction of Wolbachia-infected mosquitoes and gene-editing technologies.ConclusionThis bibliometric study underscores the critical role of interdisciplinary collaboration in advancing DENV research, identifying key trends and areas needing further exploration, including host-virus dynamics, the development and application of antiviral drugs and vaccines, and the use of artificial intelligence. It advocates for strengthened partnerships across various disciplines to effectively tackle the challenges posed by DENV.