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Major dengue epidemics throughout Nicaraguas history have been dominated by 1 of 4 dengue virus serotypes (DENV-1-4). To examine serotypes during the dengue epidemic in Nicaragua in 2022, we performed real-time genomic surveillance in-country and documented cocirculation of all 4 serotypes. We observed a shift toward co-dominance of DENV-1 and DENV-4 over previously dominant DENV-2. By analyzing 135 new full-length DENV sequences, we found that introductions underlay the resurgence: DENV-1 clustered with viruses from Ecuador in 2014 rather than those previously seen in Nicaragua; DENV-3, which last circulated locally in 2014, grouped instead with Southeast Asia strains expanding into Florida and Cuba in 2022; and new DENV-4 strains clustered within a South America lineage spreading to Florida in 2022. In contrast, DENV-2 persisted from the formerly dominant Nicaragua clade. We posit that the resurgence emerged from travel after the COVID-19 pandemic and that the resultant intensifying hyperendemicity could affect future dengue immunity and severity.

Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.

The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Here, we study dengue virus (DENV) transmission across the ecologically and demographically distinct regions or Ecuador. We analyzed province-level age-stratified dengue incidence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have age-specific distributions of hospital-seeking cases consistent with recent emergence across all provinces. To evaluate factors associated with geographic differences in DENV transmission potential, we modeled DENV vector risk using 11,693 Aedes aegypti presence points to the resolution of 1 hectare. In total, 56% of the population of Ecuador, including in provinces identified as having increasing DENV transmission in our models, live in areas with high risk of Aedes aegypti, with population size, trash collection, elevation, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.

Dengue fever virus (DENV) poses a significant public health risk in tropical and subtropical regions across the world. Although the dengue fever virus (DENV) exhibits significant genetic diversity and has the potential to evolve, there is a lack of comprehensive research on the comparative genomics and evolutionary dynamics of the virus in Pakistan. Phylogenetic analysis demonstrated the circulation of all four dengue virus serotypes (DENV-1, − 2, − 3, and − 4) with prevalent genotypes III and V within DENV-1, cosmopolitan genotype within DENV-2, genotype III within DENV-3, and genotype I within DENV-4 during 2006–2014. Based on the complete envelope region, genome-wide residue signature and genetic diversity indicate that there is a high level of genetic diversity among DENV-1 strains, while DENV-3 strains exhibit the least genetic diversity. Comparative analysis of all four DENV serotypes revealed that certain codons in DENV-2 and -4 were subject to strong purifying selection, while a few codon sites in the envelope region showed evidence of positive selection. These findings provided valuable insights into the comparative genomics and evolutionary pattern of DENV strains reported from Pakistan. Whether those characteristics conferred a fitness advantage to DENV-1 genotypes within a specific geography and time interval warrants further investigations. The findings of the current study will contribute to tracking disease dynamics, understanding virus transmission and evolution, and formulating effective disease control strategies. [ABSTRACT FROM AUTHOR]

Since its emergence in 2019, coronavirus disease (COVID-19) has spread worldwide and consumed public health resources. However, the world still has to address the burdens of other infectious diseases that continue to thrive. Countries in the tropics and neotropics, including Brazil, are affected by annual, cyclic dengue epidemics. Little is known about the impact of subsequent infections between DENV and SARS-CoV-2. Our study was performed on 400 serum samples collected from laboratory-confirmed COVID-19 patients between January and June 2021, months historically known for DENV outbreaks in Brazil. The samples were tested by serology and molecular assays for the presence of DENV and other arboviruses. While no DENV PCR results were detected, 6% were DENV IgM-positive, and 0.25% were DENV NS1-positive according to ELISA. IgM antibodies were isolated by chromatography, and 62.5% of the samples were positive for neutralizing antibodies (FRNT80) against DENV IgM, suggesting a recent infection. We also observed increased IL-10, TNF-α, and IL-1β levels in patients with overlapping SARS-CoV-2/DENV infections. Intriguingly, diabetes was the only relevant comorbidity (p=0.046). High rates of hospitalization (94.9%) and mortality (50%) were found, with a significant increase in invasive mechanical ventilatory support (86.96%) in SARS-CoV-2/DENV- infected patients, suggesting an impact on patient clinical outcomes. When analyzing previous exposure to DENV, secondary dengue patients infected with SARS-CoV-2 more frequently presented with dyspnea and respiratory distress, longer hospital and intensive care unit (ICU) stays (4 and 20.29 days, respectively) and a higher mortality rate (60%). However, a greater proportion of patients with primary DENV infection had fever and cough than patients with secondary dengue (87.50% vs. 33.33%, p=0.027 for fever). Our data demonstrate that differentiating between the two diseases is a great concern for tropical countries and should be explored to improve patient management. [ABSTRACT FROM AUTHOR]

The non-structural protein 1 (NS1), a viral toxin, is linked to serious consequences of dengue. Given its crucial role in the viral life cycle, NS1 has been a primary target for antiviral drug development. This study elucidates the mechanistic impact of specific NS1 mutations, V220D and A248V, identified by Tan and colleagues as potential inhibitors of viral replication. We developed an integrated computational framework to analyze these mutations relative to the native NS1 protein. Using conventional all-atom molecular dynamic simulations followed by site-directed in silico mutagenesis, significant alterations in protein structure were observed. Conformational ensembles over time showed average backbone deviations of 0.44 nm and 0.43 nm for V220D and A248V, respectively, compared to 0.37 nm for the wild type. Residue-wise fluctuations were higher in A248V compared to both wild type and V220D systems. Mutation-induced disruptions in the hydrogen bond network and altered protein structure graphs were also revealed. Principal component analysis and free energy landscape assessments showed the wild-type protein had a more constrained and stable conformation, whereas the mutants displayed scattered energy contours, suggesting reduced structural stability. This comprehensive assessment provides deep insight into the structural impact of NS1 mutations, informing future efforts in antiviral drug development targeting NS1. [ABSTRACT FROM AUTHOR]

ABSTRACT Arthropod‐borne flaviviruses (ABFs), transmitted by mosquitoes or ticks, are increasing due to climate change and globalization. This scoping review examines the epidemiology, clinical characteristics, diagnostics, treatment, and outcomes of ABF infection in solid organ transplant recipients (SOTRs). A database search up to January 25, 2024, focused on ABFs such as West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), Powassan virus (POWV), yellow fever virus (YFV), and Zika virus (ZIKV), limited to SOTRs.We identified 173 WNV cases from 84 studies, with 28 donor‐derived infections (DDIs). Common clinical features included fever (78.5%), altered mental status (65.1%), and weakness or paralysis (45.6%). Treatment involved reducing immunosuppression (IS) in 93 cases, with intravenous immunoglobulin (IVIG), interferon alfa‐2b, and ribavirin used in 75 cases. Seven cases involved graft loss or rejection post‐infection. WNV infection had a 23.7% mortality rate, with severe neurological complications in 43.9%For DENV infection, 386 cases from 47 studies were identified, including 14 DDI cases. Symptoms included fever (85%), myalgias (56.4%), and headache or retro‐orbital pain (34.6%). Severe dengue occurred in 50 cases (13.0%). IVIG was administered in six cases. Reduction in IS was reported in 116 patients. DENV mortality rate was 4.9%.Additionally, 26 cases of less common ABFs such as JEV, POWV, YFV, and ZIKV were described.In summary, ABF infections among SOTRs are associated with higher morbidity and mortality compared to the general population, emphasizing the need for improved preventive strategies, timely diagnosis, and optimized management protocols. [ABSTRACT FROM AUTHOR]

Background: The 4 serotypes of dengue virus (DENV1-4) can each cause potentially deadly dengue disease, and are spreading globally from tropical and subtropical areas to more temperate ones. Nepal provides a microcosm of this global phenomenon, having met each of these grim benchmarks. To better understand DENV transmission dynamics and spread into new areas, we chose to study dengue in Nepal and, in so doing, to build the onsite infrastructure needed to manage future, larger studies. Methods and results: During the 2022 dengue season, we enrolled 384 patients presenting at a hospital in Kathmandu with dengue-like symptoms; 79% of the study participants had active or recent DENV infection (NS1 antigen and IgM). To identify circulating serotypes, we screened serum from 50 of the NS1+ participants by RT-PCR and identified DENV1, 2, and 3 – with DENV1 and 3 codominant. We also performed whole-genome sequencing of DENV, for the first time in Nepal, using our new on-site capacity. Sequencing analysis demonstrated the DENV1 and 3 genomes clustered with sequences reported from India in 2019, and the DENV2 genome clustered with a sequence reported from China in 2018. Conclusion: These findings highlight DENV's geographic expansion from neighboring countries, identify China and India as the likely origin of the 2022 DENV cases in Nepal, and demonstrate the feasibility of building onsite capacity for more rapid genomic surveillance of circulating DENV. These ongoing efforts promise to protect populations in Nepal and beyond by informing the development and deployment of DENV drugs and vaccines in real time. [ABSTRACT FROM AUTHOR]

This study investigates the kinetics of interleukine-6 (IL-6) and interleukine-10 (IL-10) levels in dengue virus (DENV) infections during the febrile stage. Viremic patients were categorized into two phases based on anti-DENV IgM presence. Among 259 patients, 71% were in Phase I and 29% in Phase II. Secondary infections, accounting for 38.2% of cases, exhibited earlier elevations of IL-6 and IL-10 than primary infections, suggesting that pre-existing immune memory primes faster cytokine release. Thrombocytopenia and elevated aspartate transaminase (AST) levels were associated with Phase II, secondary infections, and hospitalization. Elevated IL-6 and IL-10 levels correlated with low platelet counts, linking them to clinical manifestations. The key finding is that IL-6 and IL-10 levels rise earlier in secondary infections compared to primary infections, whereas elevated cytokine levels typically occur later in the febrile phase. This study highlights the importance of cytokine dynamics in DENV infections, particularly during the early stages. The observation of cytokine concentration changes, especially in viremic samples, provides insights into the progression of dengue disease. Further research with broader cytokine panels is warranted to validate and expand these findings. [ABSTRACT FROM AUTHOR]

Panama is a country with endemic Dengue virus (DENV) transmission since its reintroduction in 1993. The four serotypes have circulated in the country and the region of the Americas, however, DENV-4 confirmed autochthonous cases have not been identified since 2000, despite its circulation in neighboring countries. Here, we report DENV-4 detection in Panama in the last four-month period of 2023 with cocirculation of the other serotypes, this was associated with a peak of dengue cases during the dry season even thoughmost dengue outbreaks are described in the rainy season. Complete genomes of DENV-4 allowed us to determine that cases were caused by DENV-4 genotype IIb, the same genotype as 23 years ago, with high similarity to DENV-4 sequences circulating in Nicaragua and El Salvador during 2023. This report shows the importance ofmaintaining serotype and genotype surveillance for early detection of new variants circulating in the country. [ABSTRACT FROM AUTHOR]

Dengue fever, caused by dengue virus, poses a significant global health challenge, particularly in tropical regions where Aedes aegypti serves as the primary vector. The circadian clock in Aedes aegypti governs key behavioral and physiological processes, including activity patterns, feeding behaviors, and susceptibility to dengue virus infection. This article explores the influence of circadian rhythms on the mosquito's ability to transmit dengue virus, emphasizing how the circadian regulation of gene expression, immune responses, and lipid metabolism in the mosquito vector creates temporal windows that affect viral replication efficiency. [ABSTRACT FROM AUTHOR]

Background: Yellow fever virus (YFV) and dengue virus (DENV) are among the major re-emerging arboviruses that pose a significant threat to public health. Their associated burden and prevalence can be substantially underestimated due to insufficient surveillance and inadequate diagnosis. This study aimed to determine evidence of dengue, yellow and related flaviviruses circulation among the rural human populations residing in Nguruman (Kajiado County) and Kerio Valley (Baringo County), two dryland ecosystems in the Kenyan Rift Valley. Methods: Serum samples obtained from febrile patients between 5 and 85 years through a hospital-based cross-sectional survey from July 2020 – May 2023, were screened for neutralizing antibodies to YFV, DENV-2 and related flaviviruses, West Nile virus (WNV) and Zika virus (ZIKV) via Plaque reduction neutralization test (PRNT). The study sites and important demographic characteristics were obtained using a structural questionnaire and the data analyzed and seroprevalence compared. A multinomial logistic regression model was done to predict risk for each of the most prevalent viruses with covariates; age, gender, and occupation. Results: Overall, 54.5% (50.1–59.0% 95% confidence interval (CI) of the samples tested positive for at least one of the four Flaviviruses. The percentage was significantly higher in Kerio Valley (64.34%, 184/286) than in Nguruman (40.2%, 78/194) (P<0.0001). YFV had the highest prevalence, followed by WNV (16.25%), ZIKV (5.2%), and DENV-2 (1%). Kerio Valley had a significantly higher YFV seroprevalence (51%) than Nguruman (6%) (P<0.0001), while DENV-2 was observed only in Nguruman with a low seropositivity of 2%. In contrast to Nguruman, where seropositivity rates were higher in males at 47.47% (P=0.049), in Kerio Valley, females showed considerably higher viral seropositivity at 60.82% than males (P<0001). Conclusion: The study suggests that there is significant circulation of Flaviviruses in both regions, posing a public health risk, that could potentially contribute to clinical disease. However, seropositivity rates vary for each specific site. Furthermore, there could be a risk of YFV, WNV, and ZIKV transmission in both sites with DENV transmission specifically noted in Nguruman. The study findings inform direct cost-effective actions (such as YF vaccines) and precise surveillance data of vector populations for improved disease risk prediction. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) causes millions of infections each year, and there are currently no approved antivirals. Essential oils could serve as potential candidates for developing plant-based dengue treatments. Lippia alba (Mill.) N.E. Brown essential oil (LAEO) was selected to investigate the mode of antiviral action and its effect on activated platelets. Binding affinities of 20 LAEO compounds and platelet proteins were investigated through docking analyses. LAEO showed a potent virucidal effect (IC50, 2.1 to 5.1 μg/mL) against all DENV serotypes. LAEO reduced P-selectin (from 61% to 18%) and increased survival (from 71% to 97%) in DENV-2- and DENV NS1-stimulated human platelets. Sesquiterpene hydrocarbons showed the highest binding affinities (from −7.3 to −8.0 kcal/mol) with platelet innate immune receptors such as TLR2/1, TLR4/MD-2 and αIIbβ3 integrin. The data provide a first step towards defining the potential of LAEO as a candidate for developing phytotherapeutics for dengue. [ABSTRACT FROM AUTHOR]

The epidemiologic effects of Zika virus (ZIKV) sexual transmission in virus-endemic countries remain unclear. We conducted a 2-level, linear mixed-effects logistic regression analysis by using a recently acquired population-based ZIKV and chikungunya virus (CHIKV) serologic dataset obtained from persons residing in Northeast Brazil (n = 2,070 participants). We adjusted mathematical models for housing type and age of participants; the models indicated a significantly higher likelihood of ZIKV seropositivity among persons engaged in a sexual relationship within the same household (odds ratio 1.25 [95% CI 1.00–1.55]; p = 0.047), regardless of their partner’s ZIKV serostatus, and among participants with a ZIKV-seropositive sex partner within the same household (odds ratio 1.54 [95% CI 1.18–2.01]; p = 0.002). CHIKV was also modeled as a control; no sex-associated effects were observed for CHIKV serology. Inclusion of ZIKV sexual transmission in prevention and control strategies is urgently needed, particularly in ZIKV-endemic regions.

Introduction Dengue disease represents a large and growing global threat to public health, accounting for a significant burden to health systems of endemic countries. The World Health Organization’s (WHO) Strategic Advisory Group of Experts (SAGE) and the European Medicines Agency (EMA) currently recommend the use of TAK-003 dengue vaccine in high dengue burden and transmission settings for countries considering vaccination as part of their integrated management strategy for prevention and control of Dengue.Areas covered This paper describes the main conclusions of a workshop held by the Arbovirus Committee of the Latin American Society of Pediatric Infectious Diseases (SLIPE) in November 2023, to generate consensus recommendations on the introduction of this new vaccine in the region. Considerations were made regarding the molecular epidemiology of dengue infection in the Americas and the need for more precise phylogenetic classification and correlation with clinical outcome and disease severity.Expert opinion Introduction of dengue vaccine should be considered as an strategy for health entities in the region, with participation of social sectors, scientific societies, and ministries of health that could be able to create a successful vaccination program.

ABSTRACTAs positive-sense RNA viruses, the genomes of flaviviruses serve as the template for all stages of the viral life cycle, including translation, replication, and infectious particle production. Yet, they encode just 10 proteins, suggesting that the structure and dynamics of the viral RNA itself helps shepherd the viral genome through these stages. Herein, we highlight advances in our understanding of flavivirus RNA structural elements through the lens of their impact on the viral life cycle. We highlight how RNA structures impact translation, the switch from translation to replication, negative- and positive-strand RNA synthesis, and virion assembly. Consequently, we describe three major themes regarding the roles of RNA structure in flavivirus infections: 1) providing a layer of specificity; 2) increasing the functional capacity; and 3) providing a mechanism to support genome compaction. While the interactions described herein are specific to flaviviruses, these themes appear to extend more broadly across RNA viruses.

Abstract Background The 4 serotypes of dengue virus (DENV1-4) can each cause potentially deadly dengue disease, and are spreading globally from tropical and subtropical areas to more temperate ones. Nepal provides a microcosm of this global phenomenon, having met each of these grim benchmarks. To better understand DENV transmission dynamics and spread into new areas, we chose to study dengue in Nepal and, in so doing, to build the onsite infrastructure needed to manage future, larger studies. Methods and results During the 2022 dengue season, we enrolled 384 patients presenting at a hospital in Kathmandu with dengue-like symptoms; 79% of the study participants had active or recent DENV infection (NS1 antigen and IgM). To identify circulating serotypes, we screened serum from 50 of the NS1+ participants by RT-PCR and identified DENV1, 2, and 3 – with DENV1 and 3 codominant. We also performed whole-genome sequencing of DENV, for the first time in Nepal, using our new on-site capacity. Sequencing analysis demonstrated the DENV1 and 3 genomes clustered with sequences reported from India in 2019, and the DENV2 genome clustered with a sequence reported from China in 2018. Conclusion These findings highlight DENV’s geographic expansion from neighboring countries, identify China and India as the likely origin of the 2022 DENV cases in Nepal, and demonstrate the feasibility of building onsite capacity for more rapid genomic surveillance of circulating DENV. These ongoing efforts promise to protect populations in Nepal and beyond by informing the development and deployment of DENV drugs and vaccines in real time.

We identified 3 clades of dengue virus serotype 3 belonging to genotype III isolated during 2019–2020 in Jamaica by using whole-genome sequencing and phylogenomic and phylogeographic analyses. The viruses likely originated from Asia in 2014. Newly expanded molecular surveillance efforts in Jamaica will guide appropriate public health responses.

Broad spectrum oral antivirals are urgently needed for the early treatment of many RNA viruses of clinical concern. We previously described the synthesis of 1-O-octadecyl-2-O-benzyl-glycero-3-phospho-RVn (V2043), an orally bioavailable lipid prodrug of remdesivir nucleoside (RVn, GS-441524) with broad spectrum antiviral activity against viruses with pandemic potential. Here we compared the relative activity of V2043 with new RVn lipid prodrugs containing sn-1 alkyl ether or sn-2 glycerol modifications. We found that 3-F-4-MeO-Bn, 3-CN-Bn, and 4-CN-Bn sn-2 glycerol modifications improved antiviral activity compared to V2043 when tested in vitro against clinically important RNA viruses from 5 virus families. These results support the continued development of V2043 and sn-2 glycerol modified RVn lipid prodrugs for the treatment of a broad range of RNA viruses for which there are limited therapies.

Infants less than 1 y of age experience high rates of dengue disease in dengue virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, key uncertainties exist regarding the impact of long-term shifts in birth rates, population-level infection risks, and maternal ages on the DENV immune landscape of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease.

Despite advancements in medicine and vaccination, the global death toll from dengue disease continues to rise, especially in developing countries, where modern healthcare access and prevention are limited. In the twenty-first century, dengue disease has emerged as a severe global challenge for the health sector because it severely affects more than 100 countries and causes thousands of deaths annually. This study designs an SEIR-SEI mathematical model of the dengue virus by introducing a control parameter within the mosquito population. The inclusion of this parameter enables us to determine the impact of control measures on the transmission dynamics of the dengue virus. Firstly, we ensure that all state variables are bounded and remain non-negative throughout the study. Then, we calculate the two equilibrium points, the dengue-free equilibrium (DFE) and dengue-endemic equilibrium point (DEE), of the model for further analysis. We also calculate the reproductive number R , which is a crucial threshold parameter in epidemiology. The qualitative analysis shows that the model possesses local and global stability at the DFE and DEE points if R < 1 and R > 1 , respectively. We also conduct a sensitivity analysis to identify the parameter with the most significant impact on the transmission dynamics of the dengue virus. This insight assists health policy makers in optimizing their struggles to lower the infection rates between susceptible humans and infected mosquito populations. We apply the two numerical schemes, the non-standard finite difference scheme (NSFD) and the Runga-kutta (RK4) scheme, to validate the theoretical and numerical results of the proposed SEIR-SEI dengue epidemic model. Numerical simulations are also provided in support of these results. [ABSTRACT FROM AUTHOR]

Mosquitoes of the genus Aedes are the most important arthropod disease vector. Dengue virus (DENV) and Chikungunya virus (CHIKV) are the main arboviruses distributed throughout the world. Based on entomo-virological surveillance, appropriate public health strategies can be adopted to contain cases and control outbreaks. This study aims to show the potential performance of two new molecular methods for detecting DENV serotypes and CHIKV in mosquitoes. Mosquitoes were collected in urban and sylvatic areas of Bobo-Dioulasso, Burkina Faso, between July and August 2023. DENV and CHIKV were screened using new multiplex RT-PCR and RT-qPCR methods. A total of 2150 mosquitoes were trapped, consisting of 976 Aedes (959 Ae. aegypti, 6 Ae. furcifer, and 11 Ae. vittatus) and 1174 Culex sp. These were grouped into 39 pools, with each pool containing a maximum of 30 mosquitoes. Molecular screening revealed that 7.7% (3/39) of the pools were positive for DENV. Specifically, DENV-1 was detected in one pool (1/3), and DENV-3 was found in two pools (2/3). All pools tested negative for CHIKV. The overall minimum infection rate (MIR) of DENV in this study was 3.07 (95% CI: 2.24–19.86). This study shows the usefulness of our new molecular tools for the surveillance of DENV serotypes and CHIKV.

Abstract Background Dengue infection poses a significant global health challenge, particularly in tropical and subtropical regions. Among its severe complications, Acute kidney injury (AKI) stands out due to its association with increased morbidity, mortality, and healthcare burdens. This Meta-analysis aim to identify and evaluate the predictors of AKI among dengue patients, facilitating early detection and management strategies to mitigate AKI’s impact. Methods We searched PubMed, EMBASE, and Web of Science databases, covering literature up to February 2024. We included human observational studies reporting on AKI predictors in confirmed dengue cases. Nested-Knowledge software was used for screening and data extraction. The Newcastle-Ottawa Scale was used for quality assessment. R software (V 4.3) was utilized to compute pooled odds ratios (ORs) and 95% confidence intervals (CIs) for each predictor. Results Our search yielded nine studies involving diverse geographic locations and patient demographics. A total of 9,198 patients were included in the studies, with 542 diagnosed with AKI. in which key predictors of AKI identified include severe forms of dengue (OR: 2.22, 95% CI: 1.02–3.42), male gender (OR: 3.13, 95% CI: 1.82–4.44), comorbidities such as diabetes mellitus (OR: 3.298, 95% CI: 0.274–6.322), and chronic kidney disease (OR: 2.2, 95% CI: 0.42–11.24), as well as co-infections and clinical manifestations like rhabdomyolysis and major bleeding. Conclusion Our study identifies several predictors of AKI in dengue patients. These findings indicate the importance of early identification and intervention for high-risk individuals. Future research should focus on standardizing AKI diagnostic criteria within the dengue context and exploring the mechanisms underlying these associations to improve patient care and outcomes.

Jing Zhao,&ast; Jiuxiang He,&ast; Xiaoyan Ding, Yuxin Zhou, Minchi Liu, Xiaozhong Chen, Wenxuan Quan, Dong Hua, Jun Tong, Jintao Li College of Basic Medicine, Army Medical University, Chongqing, 400038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jintao Li, College of Basic Medicine, Army Medical University, Gaotanyan Street, No. 30, Shapingba District, Chongqing, 400038, People’s Republic of China, Tel +1-86-23-68771389, Fax +1-86-23-68771391, Email ljtqms@tmmu.edu.cnBackground: The global prevalence of Dengue virus (DENV) infection poses a significant health risk, urging the need for effective vaccinations. Peptide vaccines, known for their capacity to induce comprehensive immunity against multiple virus serotypes, offer promise due to their stability, safety, and design flexibility. Spherical nucleic acid (SNA), particularly those with gold nanoparticle cores, present an attractive avenue for enhancing peptide vaccine efficacy due to their modularity and immunomodulatory properties.Methods: The spherical nucleic acid-TBB (SNA-TBB), a novel nanovaccine construct, was fabricated through the co-functionalization process of SNA with epitope peptide, targeting all four serotypes of the DENV. This innovative approach aims to enhance immunogenicity and provide broad-spectrum protection against DENV infections. The physicochemical properties of SNA-TBB were characterized using dynamic light scattering, zeta potential measurement, and transmission electron microscopy. In vitro assessments included endocytosis studies, cytotoxicity evaluation, bone marrow-dendritic cells (BMDCs) maturation and activation analysis, cytokine detection, RNA sequencing, and transcript level analysis in BMDCs. In vivo immunization studies in mice involved evaluating IgG antibody titers, serum protection against DENV infection and safety assessment of nanovaccines.Results: SNA-TBB demonstrated successful synthesis, enhanced endocytosis, and favorable physicochemical properties. In vitro assessments revealed no cytotoxicity and promoted BMDCs maturation. Cytokine analyses exhibited heightened IL-12p70, TNF-α, and IL-1β levels. Transcriptomic analysis highlighted genes linked to BMDCs maturation and immune responses. In vivo studies immunization with SNA-TBB resulted in elevated antigen-specific IgG antibody levels and conferred protection against DENV infection in neonatal mice. Evaluation of in vivo safety showed no signs of adverse effects in vital organs.Conclusion: The study demonstrates the successful development of SNA-TBB as a promising nanovaccine platform against DENV infection and highlights the potential of SNA-based peptide vaccines as a strategy for developing safe and effective antiviral immunotherapy.Keywords: nanovaccine, dengue virus, spherical nucleic acid, immunogenicity, peptide antigen

Dengue fever (DF), caused by the dengue virus (DENV), is a major public health problem worldwide, with approximately 390 million reported annual infections. The lack of specific antiviral therapies and limited means of vector control has led to the development of a dengue vaccine as a promising strategy to combat this disease. The purpose of this review is to provide a comprehensive analysis of the current status and prospects of dengue vaccines. This review describes different approaches used in dengue vaccine development, including live-attenuated, inactivated, subunit, and viral vector vaccines. Each approach is evaluated for immunogenicity, safety, and efficacy based on preclinical and clinical studies, highlighting the strengths and limitations of each vaccine candidate. Future directions and research priorities in dengue vaccine development are highlighted. In conclusion, dengue vaccines have great potential to reduce the burden of DF worldwide. However, some challenges remain regarding vaccine safety, efficacy, delivery, and availability. By addressing these challenges and leveraging advances in vaccine technology, there can be more effective control and prevention of DF and protection of public health, leading to improvement in the quality of life.

This study provides a preliminary background for the development of a viral vector vaccine for the dengue virus using genetic material encoded by dengue envelope ferritin nanoparticles. Adenoviruses were generated for the recombinant envelope of dengue virus 2 (DENV2) and the envelope human ferritin heavy chain using a two-vector adenovirus system. The primary immunostimulatory activity of the two viruses was analyzed in mice to determine the effect of envelope ferritin nanoparticles. Transfection of a shuttle vector delivered the target gene and packaging vector carrying the packaging signal, and recombinant adenoviruses (rAds) were generated and purified using an ultracentrifugation method. Transduction efficiencies of the generated adenoviruses were confirmed in A549 cells. Purified adenoviruses (8 × 106 PFU/mL) were immunized intramuscularly into 6 weeks old BALB/c mice. Subsequently, the DENV2-specific IgG titer was evaluated 1 and 4 weeks after immunization. Envelope ferritin-immunized mice showed a significant IgG response compared to envelope-only immunized mice at 1 and 4 weeks after immunization, revealing the persistence of the dengue virus-specific IgG response. This method demonstrated the capability of the viral vector vaccine to be used as a carrier for ferritin nanoparticles, instead of direct immunization with ferritin nanoparticles.

Abstract Dengue, an acute febrile disease transmitted by Aedes mosquitoes, is caused by the dengue virus (DENV), presenting a formidable challenge to global public health. By examining clues from ancient Chinese books and conducting a comprehensive review, this study elucidates the characteristics of potential dengue epidemics in China prior to 1978. This evidence indicates that China may not have experience dengue epidemics before 1840. During 1840–1949, however, it experienced a noticeable dengue occurrence and prevalence in the 1870s, 1920s, and 1940s. Then from 1949 to 1978, only sporadic reports were accounted. The disparity in the frequency of dengue occurrences across three time periods suggests that the persistent characteristic of dengue epidemics in China primarily arises from imported cases resulting from international exchanges, subsequently leading to local outbreaks influenced by global epidemic trend. This research offers a novel perspective on retrospectively examining the historical trajectory of dengue epidemics and provides valuable insights into exploration of DENV epidemic patterns. Graphical Abstract

Abstract Background Dengue 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. Results We 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. Conclusions This 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

Dengue is a highly prevalent mosquito-borne disease that is endemic in over 100 countries. It has a wider impact in terms of severity of illness and mortality risk in the absence of an effective vaccine as yet. The purpose of this study was to use meta-analysis to find out how common the dengue virus (DENV) is in India based on public data and to figure out how much of a problem. We searched, read, and reviewed about DENV in India that were available online. Forty-four cross-sectional studies were selected from the 178 records. There were reports of dengue cases in 14 out of the 28 states. Out of the patients presenting with symptoms of Dengue 27% of people were confirmed to have DENV infection with 82.29% (95% CI. 81-84%), having dengue IgM, 41.67% (95% CI: 40.16-43.43), having dengue IgG, and 23.97% (95% C.I. 14-43%), having both IgG and IgM from positive sample n=27156. Hospital-based cross-sectional studies on suspected Dengue-like illness (DLI) found that 99.48% of people had confirmed dengue out of the patients with features of DLI, and community-based studies found that 0.52% of DLI cases had dengue. The seroprevalence rates for East, South, North, and Western regions were 35.38% (95% C.I.14-31%), 11.57% (95% C.I. 2-69%), 38.10% (95% C.I. 9-61%), and 14.87% (95% C.I. 6-38%) correspondingly. DENV is interestingly spreading across the whole country, and the disease’s frequency varies a lot from place to place and from 2010-2023. However this review does not find appropriate published literature from 50% of the Indian states. The identification of IgG-class antibodies to dengue virus is indicative of prior exposure to this pathogen. Almost all immunocompetent individuals should have developed IgG antibodies against the dengue virus within three weeks of exposure. The presence of dengue virus IgM-class antibodies is indicative of an acute phase of infection. National Vector borne Disease Control Programme (NVBDCP) has some surveillance information, appropriate designed research into prevalence and risk factors for DENV infection would be required to provide adequate information for public health intervention.

Abstract Background C-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. Methods Transcripts 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. Results We 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. Conclusions The 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 Abstract

Dengue fever, an arboviral disease primarily transmitted by Aedes mosquitoes, poses a significant public health concern globally. Key vectors, such as Aedes aegypti, Aedes albopictus and Aedes cinereus, are widely distributed in tropical and subtropical regions, affecting over 140 countries. These species are also found in Iran, particularly in the southern, southeastern, and northern regions. Diagnosing dengue fever presents challenges, including differentiating it from other febrile illnesses and recognizing early warning signs of severe dengue. Symptoms typically include acute fever, warning signs of severe illness, and potential complications. The clinical progression of dengue includes three phases: the febrile phase, critical phase, and recovery phase. A comprehensive understanding of clinical manifestations, prognostic indicators, diagnostic algorithms, and laboratory methods is crucial for accurate diagnosis, risk assessment, and effective disease management. Given the absence of specific antiviral treatments or vaccines for dengue, supportive care and symptomatic treatment remain essential. This narrative review discusses the management of dengue fever, focusing on supportive care, fluid management, antipyretic and analgesic medications, and antiviral treatments. Additionally, it reviews potential future treatment strategies and emphasizes the importance of early diagnosis and prompt medical intervention in improving patient outcomes. The study also explores immunological targets, vaccine platforms, clinical trials, and future prospects for dengue vaccination. Furthermore, it presents prevention strategies targeting Aedes mosquitoes and outlines the challenges that lie ahead. By adopting a comprehensive and interdisciplinary approach, we can pave the way for advancements in the prevention and control of dengue fever related to Aedes mosquito transmission. Continued research efforts, innovative collaborations, and public health training are vital to combat dengue fever and reduce its burden on affected populations worldwide.

Abstract NS1 is an elusive dengue protein, involved in viral replication, assembly, pathogenesis, and immune evasion. Its levels in blood plasm are positively related to disease severity like thrombocytopenia, hemorrhage, and vascular leakage. Despite its pathogenic roles, NS1 is being used in various vaccine formulations due to its sequence conservancy, ability to produce protective antibodies and low risk for inducing antibody-dependent enhancement. In this study, we have used bioinformatics tools and reported literature to develop an NS1 variant (dNS1). Molecular docking studies were performed to evaluate the receptor-binding ability of the NS1 and dNS1 with TLR4. NS1 and dNS1 (153 to 312 amino acid region) genes were cloned, expressed and protein was purified followed by refolding. Docking studies showed the binding of NS1 and dNS1 with the TLR4 receptor which suggests that N and C-terminal sequences of NS1 are not critical for receptor binding. Antibodies against NS1 and dNS1 were raised in rabbits and binding affinity of anti-dNS1 anti-NS1 sera was evaluated against both NS1 and dNS1. Similar results were observed through western blotting which highlight that N and C-terminal deletion of NS1 does not compromise the immunogenic potential of dNS1 hence, supports its use in future vaccine formulations as a substitute for NS1.

Dengue fever, caused by dengue virus, is a mosquito-borne virus, which poses a significant public health threat worldwide. Fifteen countries have a water or land border with Iran. This review deals with the distribution of dengue fever in Iran’s neighboring countries and the risk of transmission to Iran. The disease and the infected Aedes mosquitoes with dengue virus have reached the borders of Iran, including Afghanistan, Pakistan, and Saudi Arabia. There are imported cases in more countries neighboring Iran, including Kuwait, Oman, Qatar, and Turkey. The disease is widespread in Sindh Province of Pakistan. While indigenous case of dengue fever has not yet been reported in Iran, its presence in nearby regions raises concerns about its potential spread due to the imported cases that have been reported.

Abstract Background Dengue fever remains a significant public health challenge in tropical and subtropical regions, with its transmission dynamics being influenced by both environmental factors and human mobility. The Dominican Republic, a biodiversity hotspot in the Caribbean, has experienced recurrent dengue outbreaks, yet detailed understanding of the virus's transmission pathways and the impact of climatic factors remains limited. This study aims to elucidate the recent transmission dynamics of the dengue virus (DENV) in the Dominican Republic, utilizing a combination of genomic sequencing and epidemiological data analysis, alongside an examination of historical climate patterns. Methods We conducted a comprehensive study involving the genomic sequencing of DENV samples collected from patients across different regions of the Dominican Republic over a two-year period. Phylogenetic analyses were performed to identify the circulation of DENV lineages and to trace transmission pathways. Epidemiological data were integrated to analyze trends in dengue incidence and distribution. Additionally, we integrated historical climate data spanning several decades to assess trends in temperature and their potential impact on DENV transmission potential. Results Our results highlight a previously unknown north–south transmission pathway within the country, with the co-circulation of multiple virus lineages. Additionally, we examine the historical climate data, revealing long-term trends towards higher theoretical potential for dengue transmission due to rising temperatures. Conclusion This multidisciplinary study reveals intricate patterns of dengue virus transmission in the Dominican Republic, characterized by the co-circulation of multiple DENV lineages and a novel transmission pathway. The observed correlation between rising temperatures and increased dengue transmission potential emphasizes the need for integrated climate-informed strategies in dengue control efforts. Our findings offer critical insights for public health authorities in the Dominican Republic and similar settings, guiding resource allocation and the development of preparedness strategies to mitigate the impacts of climate change on dengue transmission.

Within the field of Philippine folkloric medicine, the utilization of indigenous plants like Euphorbia hirta (tawa-tawa), Carica papaya (papaya), and Psidium guajava (guava) as potential dengue remedies has gained attention. Yet, limited research exists on their comprehensive effects, particularly their anti-dengue activity. This study screened 2944 phytochemicals from various Philippine plants for anti-dengue activity. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling provided 1265 compounds demonstrating pharmacokinetic profiles suitable for human use. Molecular docking targeting the dengue virus NS2b-NS3 protease’s catalytic triad (Asp 75, Ser 135, and His 51) identified ten ligands with higher docking scores than reference compounds idelalisib and nintedanib. Molecular dynamics simulations confirmed the stability of eight of these ligand–protease complexes. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analysis highlighted six ligands, including veramiline (−80.682 kJ/mol), cyclobranol (−70.943 kJ/mol), chlorogenin (−63.279 kJ/mol), 25beta-Hydroxyverazine (−61.951 kJ/mol), etiolin (−59.923 kJ/mol), and ecliptalbine (−56.932 kJ/mol) with favorable binding energies, high oral bioavailability, and drug-like properties. This integration of traditional medical knowledge with advanced computational drug discovery methods paves new pathways for the development of treatments for dengue.

Dengue fever has emerged as a major international public health concern with a dramatic global increase in its frequency over the past few decades. It may present as a mild illness to a life-threatening condition with the major pathophysiological hallmark being plasma leakage as a result of increased vascular permeability and haematological abnormalities. The unpredictable nature and progression of the disease has led to research of novel haematological markers like Immature Platelet Fraction (IPF) which may help enhance the precision and efficacy of dengue management strategies by guiding the need for blood transfusion and blood lab monitoring, decreasing financial cost and hospital stay. This review provides detailed information about the immunopathogenesis of dengue, which is responsible for the fatal complexities and also gives the definition and uses of IPF by the healthcare workers. It aims to delve into the evolving role of IPF in the management of dengue, exploring its potential applications in assessing disease severity, predicting haemorrhagic tendencies and guiding therapeutic interventions. The review informs the readers about the implications and significance of the use of IPF in the treatment of dengue and how this technique can potentially reduce disease severity by timely diagnosis and treatment.

Abstract Background Dengue fever has become a significant worldwide health concern, because of its high morbidity rate and the potential for an increase in mortality rates due to lack of adequate treatment. There is an immediate need for the development of effective medication for dengue fever. Methods Homology modeling of dengue virus (DENV) non-structural 4B (NS4B) protein was performed by SWISS-MODEL to predict the 3D structure of the protein. Structure validation was conducted using PROSA, PROCHECK, Ramachandran plot, and VERIFY-3D. MOE software was used to find out the in-Silico inhibitory potential of the five triterpenoids against the DENV-NS4B protein. Results The SWISS-MODEL was employed to predict the three-dimensional protein structure of the NS4B protein. Through molecular docking, it was found that the chosen triterpenoid NS4B protein had a high binding affinity interaction. It was observed that the NS4B protein binding energy for 15-oxoursolic acid, betulinic acid, ursolic acid, lupeol, and 3-o-acetylursolic acid were − 7.18, − 7.02, − 5.71, − 6.67 and − 8.00 kcal/mol, respectively. Conclusions NS4B protein could be a promising target which showed good interaction with tested triterpenoids which can be developed as a potential antiviral drug for controlling dengue virus pathogenesis by inhibiting viral replication. However, further investigations are necessary to validate and confirm their efficacy.

The haemorrhagic features of viral haemorrhagic fevers may be caused by common patterns of metabolic disturbances of the glucose and ascorbate homeostasis. Haemorrhages and vasculature disfunctions are a clinical feature not only of viral haemorrhagic fevers, but also in scurvy, diabetes and thrombotic microangiopathic haemolytic anaemia. Interestingly, the expression of glucose and ascorbate transporter Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate and is restricted to that very species that are susceptible to filoviruses (primates, humans and fruit bats). Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. TIM-1 and TAM receptors have been recognized to enhance entry of Ebola, Lassa and Dengue viruses and viral interferences with TIM-1 could disturb its function, disturbing the expression of Glut-1. In those species not able to synthesize ascorbate and expressing Glut-1 on erythrocytes virus could interact with Glut-1 or other functionally related protein, and the influx of glucose into the cells would be severely impaired. As a consequence, transient hyperglycemia and a marked oxidative stress coupled with the high levels of glucose in plasma would be established, and then promote the activation of NF–κB transcription, exacerbating a pro-inflammatory response mediated by cytokines and chemokines: The inability to synthesize ascorbate is an Achilles Heel when trying to counteract the oxidative stress.

Dengue, an acute febrile disease transmitted by Aedes mosquitoes, is caused by the dengue virus (DENV), presenting a formidable challenge to global public health. By examining clues from ancient Chinese books and conducting a comprehensive review, this study elucidates the characteristics of potential dengue epidemics in China prior to 1978. This evidence indicates that China may not have experience dengue epidemics before 1840. During 1840–1949, however, it experienced a noticeable dengue occurrence and prevalence in the 1870s, 1920s, and 1940s. Then from 1949 to 1978, only sporadic reports were accounted. The disparity in the frequency of dengue occurrences across three time periods suggests that the persistent characteristic of dengue epidemics in China primarily arises from imported cases resulting from international exchanges, subsequently leading to local outbreaks influenced by global epidemic trend. This research offers a novel perspective on retrospectively examining the historical trajectory of dengue epidemics and provides valuable insights into exploration of DENV epidemic patterns. [ABSTRACT FROM AUTHOR]

Background: Dengue infection poses a significant global health challenge, particularly in tropical and subtropical regions. Among its severe complications, Acute kidney injury (AKI) stands out due to its association with increased morbidity, mortality, and healthcare burdens. This Meta-analysis aim to identify and evaluate the predictors of AKI among dengue patients, facilitating early detection and management strategies to mitigate AKI's impact. Methods: We searched PubMed, EMBASE, and Web of Science databases, covering literature up to February 2024. We included human observational studies reporting on AKI predictors in confirmed dengue cases. Nested-Knowledge software was used for screening and data extraction. The Newcastle-Ottawa Scale was used for quality assessment. R software (V 4.3) was utilized to compute pooled odds ratios (ORs) and 95% confidence intervals (CIs) for each predictor. Results: Our search yielded nine studies involving diverse geographic locations and patient demographics. A total of 9,198 patients were included in the studies, with 542 diagnosed with AKI. in which key predictors of AKI identified include severe forms of dengue (OR: 2.22, 95% CI: 1.02–3.42), male gender (OR: 3.13, 95% CI: 1.82–4.44), comorbidities such as diabetes mellitus (OR: 3.298, 95% CI: 0.274–6.322), and chronic kidney disease (OR: 2.2, 95% CI: 0.42–11.24), as well as co-infections and clinical manifestations like rhabdomyolysis and major bleeding. Conclusion: Our study identifies several predictors of AKI in dengue patients. These findings indicate the importance of early identification and intervention for high-risk individuals. Future research should focus on standardizing AKI diagnostic criteria within the dengue context and exploring the mechanisms underlying these associations to improve patient care and outcomes. [ABSTRACT FROM AUTHOR]

Background: Dengue 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. Results: We 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. Conclusions: This 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. [ABSTRACT FROM AUTHOR]

Background: C-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. Methods: Transcripts 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. Results: We 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. Conclusions: The 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. [ABSTRACT FROM AUTHOR]

Dengue infection has become one of the most important mosquito-borne diseases worldwide and is caused by the dengue virus (DENV). Recently, neither patent drug, phytopharmaceutical medicine, nor standardized herbal medicine has been officially available against DENV. Dried red jujube fruit (Ziziphus jujuba) ethanol extract has been proven to have an antiviral effect, anti-inflammatory efficacy, and antioxidant properties, which have potential activity against DENV infection. This research was conducted to analyze the antiviral activity of dried red jujube fruit ethanol extract against DENV-2 in vitro. The halfmaximal cytotoxic concentration (CC50) and half-maximal inhibitory concentration (IC50) were examined on Vero cells by a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, whereas the halfmaximal effective concentration (EC50) was determined using luminescence assay. The selectivity index (SI) value was determined from the ratio of CC50 and EC50. Dried red jujube fruit ethanol extracts inhibited DENV-2 in 24.59%, 22.39%, 17.98%, 14.5%, 6.42%, and 1.28% at 80 μg/mL, 40 μg/mL, 20 μg/mL, 10 μg/ mL, 5 μg/mL, and 2.5 μg/mL, respectively. The extract exhibited antiviral activity against DENV-2, showing a CC50 of 67.73 μg/mL, an IC50 value of 166.18 μg/mL, and an EC50 of 64.87 μg/mL, with an SI of 1.04. The LD50 value was 707.95 mg/kg. Dried red jujube fruit ethanol extract could be a potential candidate for developing an antiviral against DENV-2. [ABSTRACT FROM AUTHOR]

Simple Summary: Dengue fever is one of the major public health issues in tropical and subtropical regions. To prevent infection by the Dengue Virus, the World Health Organization has approved two dengue vaccines, Dengvaxia and TV003/TV005. But, unfortunately, the vaccines face challenges such as lower effectiveness and antibody-dependent enhancement (ADE). To address these concerns, we have designed a new vaccine, PSDV-2, with optimized B- and T-cell epitopes using an in silico approach. This design prioritizes high antigenicity and immunogenicity while minimizing risks such as allergenicity, toxicity, and ADE. In simulations, PSDV-2 bound strongly to immune receptors TLRs 4 and 2 and triggered a strong immune response. Although further testing is needed to confirm the effectiveness and safety of PSDV-2, our design offers a promising alternative option for dengue fever prevention, potentially contributing to an improvement in global health. Dengue virus poses a significant global health challenge, particularly in tropical and subtropical regions. Despite the urgent demand for vaccines in the control of the disease, the two approved vaccines, Dengvaxia and TV003/TV005, there are current questions regarding their effectiveness due to an increased risk of antibody-dependent enhancement (ADE) and reduced protection. These challenges have underscored the need for further development of improved vaccines for Dengue Virus. This study presents a new design using an in silico approach to generate a more effective dengue vaccine. Initially, our design process began with the collection of Dengue polyprotein sequences from 10 representative countries worldwide. And then conserved fragments of viral proteins were retrieved as the bases for epitope screening. The selection of epitopes was then carried out with criteria such as antigenicity, immunogenicity, and binding affinity with MHC molecules, while the exclusion criteria were according to their allergenicity, toxicity, and potential for antibody-dependent enhancement. We then constructed a core antigen with the selected epitopes and linked the outcomes with distinct adjuvant proteins, resulting in three candidate vaccines: PSDV-1, PSDV-2, and PSDV-3. Among these, PSDV-2 was selected for further validation due to its superior physicochemical and structural properties. Extensive simulations demonstrated that PSDV-2 exhibited strong binding to pattern recognition receptors, high stability, and robust immune induction, confirming its potential as a high-quality vaccine candidate. For its recombinant expression, a plasmid was subsequently designed. Our new vaccine design offers a promising additional option for Dengue virus protection. Further experimental validations will be conducted to confirm its protective efficacy and safety. [ABSTRACT FROM AUTHOR]

This study provides a preliminary background for the development of a viral vector vaccine for the dengue virus using genetic material encoded by dengue envelope ferritin nanoparticles. Adenoviruses were generated for the recombinant envelope of dengue virus 2 (DENV2) and the envelope human ferritin heavy chain using a two-vector adenovirus system. The primary immunostimulatory activity of the two viruses was analyzed in mice to determine the effect of envelope ferritin nanoparticles. Transfection of a shuttle vector delivered the target gene and packaging vector carrying the packaging signal, and recombinant adenoviruses (rAds) were generated and purified using an ultracentrifugation method. Transduction efficiencies of the generated adenoviruses were confirmed in A549 cells. Purified adenoviruses (8 × 106 PFU/mL) were immunized intramuscularly into 6 weeks old BALB/c mice. Subsequently, the DENV2-specific IgG titer was evaluated 1 and 4 weeks after immunization. Envelope ferritin-immunized mice showed a significant IgG response compared to envelope-only immunized mice at 1 and 4 weeks after immunization, revealing the persistence of the dengue virus-specific IgG response. This method demonstrated the capability of the viral vector vaccine to be used as a carrier for ferritin nanoparticles, instead of direct immunization with ferritin nanoparticles. [ABSTRACT FROM AUTHOR]

Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design. [ABSTRACT FROM AUTHOR]

Dengue is a highly prevalent mosquito-borne disease that is endemic in over 100 countries. It has a wider impact in terms of severity of illness and mortality risk in the absence of an effective vaccine as yet. The purpose of this study was to use meta-analysis to find out how common the dengue virus (DENV) is in India based on public data and to figure out how much of a problem. We searched, read, and reviewed about DENV in India that were available online. Forty-four cross-sectional studies were selected from the 178 records. There were reports of dengue cases in 14 out of the 28 states. Out of the patients presenting with symptoms of Dengue 27% of people were confirmed to have DENV infection with 82.29% (95% CI. 81-84%), having dengue IgM, 41.67% (95% CI: 40.16-43.43), having dengue IgG, and 23.97% (95% C.I. 14-43%), having both IgG and IgM from positive sample n=27156. Hospitalbased cross-sectional studies on suspected Dengue-like illness (DLI) found that 99.48% of people had confirmed dengue out of the patients with features of DLI, and community-based studies found that 0.52% of DLI cases had dengue. The seroprevalence rates for East, South, North, and Western regions were 35.38% (95% C.I.14-31%), 11.57% (95% C.I. 2-69%), 38.10% (95% C.I. 9-61%), and 14.87% (95% C.I. 6-38%) correspondingly. DENV is interestingly spreading across the whole country, and the disease's frequency varies a lot from place to place and from 2010-2023. However this review does not find appropriate published literature from 50% of the Indian states. The identification of IgG-class antibodies to dengue virus is indicative of prior exposure to this pathogen. Almost all immunocompetent individuals should have developed IgG antibodies against the dengue virus within three weeks of exposure. The presence of dengue virus IgM-class antibodies is indicative of an acute phase of infection. National Vector borne Disease Control Programme (NVBDCP) has some surveillance information, appropriate designed research into prevalence and risk factors for DENV infection would be required to provide adequate information for public health intervention. [ABSTRACT FROM AUTHOR]

Dengue is an important vector-borne disease occurring globally. Dengue virus (DENV) infection can result in a potentially life-threatening disease. To date, no DENV-specific antiviral treatment is available. Moreover, an equally effective panserotype dengue virus vaccine is not available. Recently, two DENV vaccines, Dengvaxia and Qdenga, were licensed for limited use. However, none of them have been approved in Bangladesh. DENV is transmitted by Aedes mosquitoes, and global warming caused by climate change favoring Aedes breeding plays an important role in increasing DENV infections in Bangladesh. Dengue is a serious public health concern in Bangladesh. In the year 2023, Bangladesh witnessed its largest dengue outbreak, with the highest number of dengue cases (n  =  321,179) and dengue-related deaths (n  =  1,705) in a single epidemic year. There is an increased risk of severe dengue in individuals with preexisting DENV-specific immunoglobulin G if the individuals become infected with different DENV serotypes. To date, vector control has remained the mainstay for controlling dengue; therefore, an immediate, strengthened, and effective vector control program is critical and should be regularly performed for controlling dengue outbreaks in Bangladesh. In addition, the use of DENV vaccine in curbing dengue epidemics in Bangladesh requires more consideration and judgment by the respective authority of Bangladesh. This review provides perspectives on the control and prevention of dengue outbreaks. We also discuss the challenges of DENV vaccine use to reduce dengue epidemics infection in Bangladesh. [ABSTRACT FROM AUTHOR]

Arthropod‐borne viruses, such as dengue virus (DENV), pose significant global health threats, with DENV alone infecting around 400 million people annually and causing outbreaks beyond endemic regions. This study aimed to enhance serological diagnosis and discover new drugs by identifying immunogenic protein regions of DENV. Utilizing a comprehensive approach, the study focused on peptides capable of distinguishing DENV from other flavivirus infections through serological analyses. Over 200 patients with confirmed arbovirus infection were profiled using high‐density pan flavivirus peptide arrays comprising 6253 peptides and the computational method matrix of local coupling energy (MLCE). Twenty‐four peptides from nonstructural and structural viral proteins were identified as specifically recognized by individuals with DENV infection. Six peptides were confirmed to distinguish DENV from Zika virus (ZIKV), West Nile virus (WNV), Yellow Fever virus (YFV), Usutu virus (USUV), and Chikungunya virus (CHIKV) infections, as well as healthy controls. Moreover, the combination of two immunogenic peptides emerged as a potential serum biomarker for DENV infection. These peptides, mapping to highly accessible regions on protein structures, show promise for diagnostic and prophylactic strategies against flavivirus infections. The described methodology holds broader applicability in the serodiagnosis of infectious diseases. [ABSTRACT FROM AUTHOR]

Dengue viruses are the causative agents of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, which are mainly transmitted by Aedes aegypti and Aedes albopictus mosquitoes, and cost billions of dollars annually in patient treatment and mosquito control. Progress in understanding DENV pathogenesis and developing effective treatments has been hampered by the lack of a suitable small pathological animal model. Until now, the candidate vaccine, antibody, and drug for DENV have not been effectively evaluated. Here, we analyzed the pathogenicity of DENV‐1 in type Ⅰ and type Ⅱ interferon receptor‐deficient mice (AGB6) by intraperitoneal inoculation. Infected mice showed such neurological symptoms as opisthotonus, hunching, ataxia, and paralysis of one or both hind limbs. Viremia can be detected 3 days after infection. It was found that 6.98 × 103 PFU or higher dose induce 100% mortality. To determine the cause of lethality in mice, heart, liver, spleen, lung, kidney, intestinal, and brain tissues were collected from AGB6 mice (at an attack dose of 6.98 × 103 PFU) for RNA quantification, and it was found that the viral load in brain tissues peaked at moribund states (14 dpi) and that the viral loads in the other tissues and organs decreased over time. Significant histopathologic changes were observed in brain tissue (hippocampal region and cerebral cortex). Hematological analysis showed hemorrhage and hemoconcentration in infected mice. DENV‐1 can be isolated from the brain tissue of infected mice. Subsequently, brain tissue transcriptome sequencing was performed to assess host response characteristics in infected AGB6 mice. Transcriptional patterns in brain tissue suggest that aberrant expression of pro‐inflammatory cytokines induces antiviral responses and tissue damage. Screening of hub genes and their characterization by qPCR and ELISA, it was hypothesized that IL‐6 and IFN‐γ might be the key factors in dengue virus‐induced inflammatory response. Therefore, this study provides an opportunity to decipher certain aspects of dengue pathogenesis further and provides a new platform for drug, antibody, and vaccine testing. [ABSTRACT FROM AUTHOR]