This chapter examines the immunological mechanisms underlying the cross-reactivity and immune enhancement in dengue and how they influence the clinical outcomes. The four DENV serotypes (DENV-1 to DENV-4) share high genetic and antigenic similarity, leading to antibodies and T cells that can recognize multiple serotypes. While this cross-reactive immunity can confer partial or transient protection, it can also result in antibody-dependent enhancement (ADE), wherein non-neutralizing antibodies facilitate viral entry into immune cells, increasing the likelihood of severe disease in secondary infections and in infants carrying maternal anti-DENV antibodies. Furthermore, cross-reactivity with other flaviviruses, such as ZIKV, complicates serological diagnosis by producing false-positive results and uncertain prior exposure histories. These complexities extend to vaccine design, which must induce effective immunity against all four DENV serotypes while minimizing ADE risk. Epidemiological studies confirm that secondary infections, especially when antibody levels have waned, carry an elevated risk of severe clinical manifestations. However, the timing between infections and the specific serotype involved can modulate these outcomes. A thorough understanding of cross-reactivity and immune enhancement is therefore pivotal for advancing diagnostic accuracy, guiding patient care, and informing vaccine strategies and public health policies to better control dengue globally.

Dengue is an important tropical disease with considerable global impact. Despite this, there remains an urgent need for reliable biomarkers to predict disease severity, as well as effective antiviral drugs and targeted treatments. In this study, we conducted a comprehensive profiling of 41 plasma mediators in patients with asymptomatic dengue (AD) and symptomatic dengue (SD), which includes mild dengue fever (DF) and severe dengue hemorrhagic fever (DHF). Our findings revealed that the levels of nearly all measured mediators were consistently lower in AD compared to SD patients, suggesting a potential protective cytokine response signature. Time-course cytokine analysis in SD shown significantly elevated levels of pro-inflammatory cytokines and chemokines associated with inflammation and viral clearance upon the acute phase, while various growth factors were elevated during the convalescence. Notably, we identified elevated IL-15 levels in DHF patients three days before fever subsidence, highlighting its potential as an early prognostic biomarker for severe disease outcomes. Furthermore, prolonged high levels of IL-8 and IP-10 in DHF during the critical period may contribute to dengue immunopathogenesis. This study advances the understanding of cytokine dynamics in the natural course of human dengue infection, providing valuable insights for the development of targeted treatments and prognostic biomarkers.

The World Health Organization (WHO) reports a rising global incidence of dengue and severe outcomes among the elderly. This study investigates the differences in dengue characteristics between elderly and non-elderly patients and identifies mortality risk factors among elderly dengue patients.

We conducted a retrospective study of adults (≥20 years) with dengue virus (DENV) infection at two medical centers from 2002 to 2018. Participants were divided into non-elderly (20-64 years) and elderly (≥65 years) groups.

A total of 1274 patients with laboratory-confirmed dengue were included in the study, of whom 373 (29.3 %) were classified as elderly. The majority of patients (67.5 %) were infected with DENV-2. In the overall cohort, age ≥65 years was identified as an independent predictor of mortality. Compared with non-elderly patients, elderly individuals exhibited significantly lower frequencies of classical dengue symptoms (e.g., fever, myalgia, bone pain, rash), but experienced higher rates of severe dengue, longer hospital stays, and more frequent complications, including acute kidney injury, severe hepatitis, bacteremia, pneumonia, and acute respiratory failure. The mortality rate was significantly higher among elderly patients (18 %) compared to non-elderly patients (2.7 %). Multivariate analysis among the elderly subgroup identified altered consciousness and pleural effusion at presentation, along with the development of acute kidney injury, severe hepatitis, and pneumonia during hospitalization, as independent predictors of mortality.

The current WHO criteria may be insufficient for the timely identification of dengue in the elderly population. Excess mortality in this group underscores the urgent need for updated guidelines. Neurological symptoms, pleural effusion at presentation, and organ impairment during hospitalization are key predictors of mortality in elderly dengue patients.

Dengue virus (DENV) infection imposes a significant global health burden, driven by its ability to manipulate host cellular processes to facilitate replication and evade immune defenses. This review explores the complex interplay between DENV, host immunometabolism, and signaling pathways. DENV induces metabolic reprogramming, including glycolytic upregulation, lipid droplet utilization through lipophagy, and alterations in amino acid metabolism, to fulfill its energy and biosynthetic needs. The virus also disrupts mitochondrial dynamics, leading to increased reactive oxygen species (ROS) production, which modulates immune responses but may also contribute to oxidative stress and severe pathology. Concurrently, DENV hijacks host signaling pathways, including PI3K/Akt, NF-κB, and JAK/STAT, to suppress apoptosis, evade type I interferon responses, and drive pro-inflammatory cytokine production. The interplay between these signaling and metabolic pathways highlights a dual role of host processes: enabling viral replication while activating antiviral immune responses. The review also examines potential therapeutic strategies targeting metabolic and signaling pathways to combat DENV infection, including glycolysis inhibitors, lipid metabolism modulators, and host-directed therapies. While significant progress has been made in understanding DENV-induced immunometabolism, further research is needed to elucidate the precise molecular mechanisms and translate these findings into clinical applications. This study underscores the importance of integrating metabolic and signaling insights to identify novel therapeutic targets against DENV and related flaviviruses, addressing the critical need for effective antiviral interventions.

The disruption of natural ecosystems caused by climate change and human activity is amplifying the risk of zoonotic spillover, presenting a growing global health threat. In the past two decades, the emergence of multiple zoonotic viruses has exposed critical gaps in our ability to predict epidemic trajectories and implement effective interventions. RNA viruses, in particular, are challenging to control due to their high mutation rates and ability to adapt and evade immune defenses. To better prepare for future outbreaks, it is vital that we deepen our understanding of the factors driving viral emergence, transmission, and persistence in human populations. Specifically, deciphering the interactions between antibody-mediated immunity and viral evolution will be key. In this perspective, we explore these dynamic relationships and highlight research priorities that may guide the development of more effective strategies to mitigate the impact of emerging infectious diseases.

Previously we identified a complex of non-structural protein (NS) 1 - Thrombin (NST) in dengue infected patients. Here, we investigated how the concentration of NS1 and NST differ in various dengue severity levels as well as their demographic and clinical features. Several comorbid (hypertension, diabetes, and chronic renal failure) often found in dengue patients were also measured and analyzed.

A total of 86 dengue patients (52 not severe and 34 severe), were enrolled and had their blood taken. Blood samples were further verified for clinical blood parameters, including liver and renal function tests and serologic assays (NS1 and NST). Patients' severity was grouped based on WHO 2009 classification, which separates patients into dengue without warning signs (DNWS), dengue with warning signs (DWWS), and severe dengue (SD). DWWS is explained as DNWS with warning signs (persistent abdominal pain, persistent vomiting, liver enlargement, bleeding (any kind), fatigue, and restlessness). SD are those with severe plasma leakage, severe bleeding, or severe organ impairment. Multivariate regression analysis was used to predict the role of NST on the dengue severity development and receiver operating characteristic (AUROC) test was utilized to evaluate separability.

The analysis revealed that NS1 significantly impacts the disease outcome (p 0.018, OR = 2.467 (1.171-5.197)) but not beyond the effect through NST (p 0.108, OR = 0.085 (0.004-1.719)). We also prove that NST was a better severity biomarker compared to NS1, as it can predict progression from DNWS to DWWS (AUC: NS1 = 0.771∗∗, NST = 0.81∗∗) and SD (AUC: NS1 = 0.607, NST = 0.754∗) significantly.

This finding suggests the importance of NST in mediating the NS1 effect to promote dengue severity progression and its promising capability as an acute stage dengue severity biomarker.

Co-infection with multiple DENV serotypes can affect human immune status and complicate the clinical presentation and management of dengue patients, so understanding the prevalence and dynamics of co-infection is important for effective dengue control. We aimed to identify and characterize DENV co-infection patterns in field-caught mosquitoes and dengue patients. This study was conducted in northeastern Thailand between June 2016 to August 2019. Female Aedes mosquitos collected from and around dengue patient's houses were analyzed for DENV infection and presence of serotypes using RT-PCR. DENV serotyping was successful in 154 (39.49%) of human and 165 (14.26%) of mosquito samples. Prevalence of DENV co-infection in patients and mosquitoes was 22.73% (35 cases) and 28.48% (47 samples), respectively. Co-infection with multiple serotypes were double (human 88.57%, mosquito 89.36%), triple (human 5.72%, mosquito 10.64%) and quadruple (human 5.72%, mosquito 0%) infections. Concurrent infection was different between hosts and concurrence patterns of DENV serotype in each host mostly composed of the predominant serotype of the detected year. This is the first report that show DENV co-infection patterns in field-caught mosquito and in dengue fever patients with combinations of triple and quadruple serotypes in Thailand. These finding are potentially useful for understanding shifts in serotypes, concurrent DENV infection patterns, vaccine development, and further research on the ability of vectors to transmit multiple serotypes.

Dengue, a vector-borne disease driven by climate change, urbanization, and the adaptation of its vector, Aedes aegypti, poses a significant public health challenge. This study analyzed 23 years (2000-2022) of epidemiological data from Peru to examine the temporal and spatial drivers influencing dengue reported cases. Using secondary data from the Peruvian Ministry of Health, 501,027 cases were stratified by clinical severity, gender, geographic distribution, and temporal trends. The Amazonian and coastal regions, particularly Loreto, Ucayali, and Piura, bore the highest burden, collectively accounting for more than 60% of cases during epidemic years. Seasonal spikes in transmission consistently aligned with the rainy season, underscoring the dependence of Aedes aegypti proliferation on climatic conditions. The analysis revealed progressive geographic expansion of dengue into previously low-risk areas, including Andean highlands and peri-urban zones, driven by climatic shifts and unregulated urbanization. Gender-based comparisons indicated a higher overall case burden among females, though severe forms of dengue were unequally observed in males, particularly in rural areas. Clinical classifications highlighted that 78% of cases presented without warning signs, 18% with warning signs, and 4% as severe dengue. Socioeconomic factors, such as inadequate sanitation, urban slums, and water storage practices, contributed significantly to vector breeding in high-burden areas. Moreover, the role of extreme climatic events, including El Niño, exacerbated outbreak intensity and duration. The findings emphasize the urgent need for innovative approaches and provides actionable insights into regional dynamics and highlights critical areas for research, including predictive climate-disease modeling and the integration of molecular surveillance. These strategies are essential to mitigating the growing dengue burden and strengthening public health systems in Peru and similar endemic regions.

Dengue, the fastest-spreading vector-borne disease (VBD), significantly burdens global health systems. This study analyzed the trends in the global burden of dengue from 1990 to 2021, utilizing data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021).

We retrieved data from GBD 2021 regarding dengue, including the number of incidences and age-standardized incidence rate (ASIR), the number of deaths and age-standardized death rate (ASDR), disability-adjusted life-years (DALYs) and age-standardized DALYs. The estimated annual percentage change (EAPC) of ASIR, ASDR, and standardized DALYs rate was calculated to quantify trends over time. In addition, the correlations between dengue burden and sea level rise, as well as the Socio-Demographic Index (SDI), were evaluated. In this study, it was observed that from 1990 to 2021, the global incidence of dengue escalated from 26.45 million to 58.96 million cases, accompanied by an increase in related deaths from 14,315 to 29,075, and DALYs rising from 1.25 million to 2.08 million years. These data collectively indicate that the disease burden approximately doubled, with South Asia, Southeast Asia, and tropical Latin America being the most severely affected regions. The disease burden remained substantial in middle and low-middle-SDI regions, whereas high-middle and high SDI regions experienced pronounced growth rates in ASIR, ASDR, and age-standardized DALYs rate. Adolescents and the elderly showed higher incidence, yet children under 5 had the highest DALYs. Correlation analyses revealed an inverted U-shaped relationship between the SDI and both the ASDR and age-standardized DALYs rate, and changes in sea level height strongly correlated with the overall dengue burden.

The global dengue burden has surged due to climate change, vector transmission, and population mobility. Increased focus and tailored control strategies are essential, particularly in South Asia, Southeast Asia, and Latin America.

In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.

Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.

The febrile illness caused by dengue is a global public health problem whose incidence is increasing. This infection can range from mild fever to severe illness with plasma leakage and shock; therefore, biomarkers of severity are urgently needed to elucidate the pathological mechanism of the disease. To explore the levels of interleukin (IL)-10 and interferon (IFN)-β in children with dengue to identify these proteins as biomarkers of severity. This study compared the serum levels of IL-10 and IFN-β in 208 Colombian paediatric patients with different degrees of severity of dengue virus infection. A total of three study groups (dengue without warning signs, dengue with warning signs, and severe dengue) were designated according to the World Health Organization classification system. Serotype type 2 was the most prevalent type, and the most frequently reported symptom was vomiting, followed by abdominal pain. Platelet values, aspartate transaminase and alanine transaminase levels and clotting times were the most altered laboratory parameters among the study groups and were more pathological in patients with severe dengue. In addition, IL-10 levels were significantly higher in those with severe dengue than in those with milder forms of infection (P < .05), and IFN-β levels were much lower in the group of patients with severe dengue than in the group with dengue without warning signs (P < .05). These results demonstrate differences in immune responses to dengue infections and suggest several molecular targets for the future development of biomarkers that can serve as diagnostic and prognostic tools for the severity of dengue disease.

Dengue, caused by four serotypes of dengue viruses (DENV-1 to DENV-4), is the most prevalent and widely mosquito-borne viral disease affecting humans. Dengue virus (DENV) infection has been reported in over 100 countries, and approximately half of the world's population is now at risk. The paucity of universally licensed DENV vaccines highlights the urgent need to address this public health concern. Action and atten-tion to antibody-dependent enhancement increase the difficulty of vaccine development. With the worsen-ing dengue fever epidemic, Dengvaxia® (CYD-TDV) and Qdenga® (TAK-003) have been approved for use in specific populations in affected areas. However, these vaccines do not provide a balanced immune response to all four DENV serotypes and the vaccination cannot cover all populations. There is still a need to develop a safe, broad-spectrum, and effective vaccine to address the increasing number of dengue cases worldwide. This review provides an overview of the existing DENV vaccines, as well as potential candidates for future studies on DENV vaccine development, and discusses the challenges and possible solutions in the field.

Cytokines are soluble signaling proteins that regulate inflammation and coordinate immune responses. Serum cytokine panels are increasingly used in medical practice, yet our understanding of cytokines as biomarkers for disease remains limited.

We sought to analyze real-world single-center use of a multiplexed cytokine panel, correlate its results with diagnosis and severity, and explore its use in pediatric practice.

A multiplexed cytokine panel, able to return same-day results, was implemented in April 2020 at the Children's Hospital of Philadelphia (Philadelphia, Pa) and its performance was validated for clinical use. Coded patient data were collected using the REDCap database, and correlations between cytokine levels and outcomes of interest were analyzed retrospectively.

Cytokine levels correlate with acuity of care, with patients admitted to the pediatric intensive care unit having the highest cytokine values. Patients with familial hemophagocytic lymphohistiocytosis (fHLH) showed prominent peaks in IFN-γ, IL-10, and TNF, whereas patients with sepsis exhibited high IL-6 and IL-8 with relatively modest IFN-γ. Cytokine release syndrome (CRS) after chimeric antigen receptor T-cell therapy often demonstrated pan-panel positivity at peak levels, with a similar pattern as that of fHLH. A ratio of [IFN-γ] + [IL-10]/[IL-6] + [IL-8] levels was able to distinguish fHLH and CRS from severe sepsis.

Cytokine levels correlate with severity of illness and can help differentiate between syndromes that present similarly, including fHLH and CRS compared with sepsis. Cytokine panels can be used as biomarkers to inform diagnosis and management decisions, but significant work remains to dissect complex clinical patterns of disease.

Understanding how immune history influences influenza immunity is essential for developing effective vaccines and therapeutic strategies. This study examines the antigenic imprinting of influenza hemagglutinin (HA) and neuraminidase (NA) using a mouse model with sequential infections by H1N1 virus strains exhibiting substantial antigenic differences in HA. In our pre-2009 influenza infection model, we observed that mice with more extensive infection histories produced higher levels of functional NA-inhibiting antibodies (NAI). However, following further infection with the 2009 pandemic H1N1 strain, these mice demonstrated a reduced NAI to the challenged virus. Interestingly, prior exposure to older strains resulted in a lower HA antibody response (neutralization and HAI) to the challenged virus in both pre- and post-2009 scenarios, potentially due to faster viral clearance facilitated by immune memory recall. Overall, our findings reveal distinct trajectories in HA and NA immune responses, suggesting that immune imprinting can differentially impact these proteins based on the extent of antigenic variation in influenza viruses.

Influenza viruses continue to pose a significant threat to human health, with vaccine effectiveness remaining a persistent challenge. Individual immune history is a crucial factor that can influence antibody responses to subsequent influenza exposures. While many studies have explored how pre-existing antibodies shape the induction of anti-HA antibodies following influenza virus infections or vaccinations, the impact on anti-NA antibodies has been less extensively studied. Using a mouse model, our study demonstrates that within pre-2009 H1N1 strains, an extensive immune history negatively impacted anti-HA antibody responses but enhanced anti-NA antibody responses. However, in response to the 2009 pandemic H1N1 strain, which experienced an antigenic shift, both anti-HA and anti-NA antibody responses were hindered by antibodies from prior pre-2009 H1N1 virus infections. These findings provide important insights into how antigenic imprinting affects both anti-HA and anti-NA antibody responses and underscore the need to consider immune history in developing more effective influenza vaccination strategies.

Dengue-associated acute liver failure (ALF) poses a significant risk for mortality, especially in regions lacking access to liver transplantation. Although Plasma Exchange (PLEX) is recognized as a potential therapeutic intervention for dengue-associated ALF, data on its efficacy remain limited. This systematic review aimed to comprehensively examine the literature on PLEX and other combination therapies for dengue-associated ALF. It focused on assessing their effectiveness, safety profile, and potential implications for therapeutic interventions.

In this study, we conducted a systematic review to assess the efficacy and safety of PLEX and other combination therapies in patients with dengue-associated ALF. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria were used to search the PubMed, Scopus, Embase, Ovid, and Google Scholar databases. Studies published in English between 2019 and May 2024 were included. The titles and abstracts were reviewed for discrepancies, and any differences were resolved through discussion.

Among the 713 studies assessed for review, 9 met the eligibility criteria. Studies have demonstrated that PLEX, both alone and in combination with other therapies, such as continuous renal replacement therapy (CRRT), improves liver function, survival rates, and neurological outcomes in patients with dengue virus. Both high- and low-volume plasma exchanges were effective.

This systematic review highlights the beneficial role of PLEX and the potential benefits of combination therapies in the treatment of rare and severe forms of dengue-associated ALF. However, given the limited sample sizes and the necessity for well-designed studies, further investigations are needed to determine the optimal volume of PLEX and the efficacy of additional therapeutic strategies.

Dengue fever is a significant health concern globally, especially in tropical regions. Identifying reliable markers for severe dengue, such as hypoalbuminemia, is crucial for early diagnosis and treatment.

This review systematically explores the association between hypoalbuminemia and severe dengue. We searched databases including PubMed, Embase, Scopus, Cochrane, and Web of Science until 28 December 2023, focusing on studies that reported albumin levels in dengue patients. Our selection criteria aimed at observational studies, from which data extraction and quality assessment were performed using Nested- Knowledge and the Newcastle-Ottawa Scale.

A meta-analysis of 17 studies involving 974 severe and 18,496 non-severe dengue patients identified a standardized mean difference (SMD) in albumin levels of -1.625 g/dL (95% CI: -3.618 to -0.369). Subgroup analysis indicated more pronounced hypoalbuminemia in pediatric patients, with a pooled SMD of -1.08 g/dL (95% CI: -1.71 to -0.45). Our analysis demonstrated the link between hypoalbuminemia and severe dengue, indicating a significant pooled relative risk of 2.286, within 95% CI 1.308 to 3.996.

The study confirms hypoalbuminemia as a significant predictor of severe dengue. Recognizing hypoalbuminemia in dengue patients can aid clinicians in forecasting the severity, potentially improving patient outcomes through targeted therapeutic strategies.

Arboviruses are a significant threat to global public health, with outbreaks occurring worldwide. Toll-like receptors (TLRs) play a crucial role in the innate immune response against these viruses by recognizing pathogen-associated molecular patterns and initiating an inflammatory response. Significantly, TLRs commonly implicated in the immune response against viral infections include TLR2, TLR4, TLR6, TLR3, TLR7, and TLR8; limiting or allowing them to replicate and spread within the host. Modulating TLRs has emerged as a promising approach to combat arbovirus infections. This review summarizes recent advances in TLR modulation as a therapeutic target in arbovirus infections. Studies have shown that the activation of TLRs can enhance the immune response against arbovirus infections, leading to increased viral clearance and protection against disease. Conversely, inhibition of TLRs can reduce the excessive inflammation and tissue damage associated with arbovirus infection. Modulating TLRs represents a potential therapeutic strategy to combat arbovirus infections.

Respiratory viral co-infections present significant challenges in clinical settings due to their impact on disease severity and patient outcomes. Current diagnostic methods often miss these co-infections, complicating the epidemiology and management of these cases. Research, primarily conducted in vitro and in vivo, suggests that co-infections can lead to more severe illnesses, increased hospitalization rates, and greater healthcare utilization, especially in high-risk groups such as children, the elderly, and immunocompromised individuals. Common co-infection patterns, risk factors, and their impact on disease dynamics highlight the need for advanced diagnostic techniques and tailored therapeutic strategies. Understanding the virological interactions and immune response modulation during co-infections is crucial for developing effective public health interventions and improving patient outcomes. Future research should focus on the molecular mechanisms of co-infection and the development of specific therapies to mitigate the adverse effects of these complex infections.

Mosquito-borne viral infections are on the rise worldwide and can lead to severe symptoms such as haemorrhage, encephalitis, arthritis or microcephaly. A protective immune response following mosquito-borne viral infections requires the generation of a controlled and balanced immune response leading to viral clearance without immunopathology. Here, regulatory T cells play a central role in restoring immune homeostasis. In current review, we aim to provide an overview and summary of the phenotypes of FOXP3+ Tregs in various mosquito-borne arboviral disease, their association with disease severity and their functional characteristics. Furthermore, we discuss the role of cytokines and Tregs in the immunopathogenesis of mosquito-borne infections. Lastly, we discuss possible novel lines of research which could provide additional insight into the role of Tregs in mosquito-borne viral infections in order to develop novel therapeutic approaches or vaccination strategies.

Millions of cases of dengue virus (DENV) infection yearly from Aedes mosquitoes stress the need for effective antivirals. No current drug effectively combats dengue efficiently. Transient immunity and severe risks highlight the need for broad-spectrum antivirals targeting all serotypes of DENV. Niclosamide, an antiparasitic, shows promising antiviral activity against the dengue virus, but enhancing its bioavailability is challenging. To overcome this issue and enable niclosamide to address the global dengue problem, nanoengineered niclosamides can be the solution. Not only does it address cost issues but also with its broad-spectrum antiviral effects nanoengineered niclosamide offers hope in addressing the current health crisis associated with DENV and will play a crucial role in combating other arboviruses as well.

Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is one of the mechanisms contributing to increased severity during heterotypic, secondary infection. The complement protein C1q has been shown to reduce the magnitude of ADE in vitro. Therefore, we investigated the mechanisms of C1q modulation of ADE, focusing on processes of viral entry. Using a model of ADE of DENV-1 infection in human myeloid cell lines in the presence of monoclonal antibodies, 4G2 and 2H2, we found that C1q produced nearly a 40-fold reduction of ADE of DENV-1 in K562 cells, but had no effect in U937 cells. In K562 cells, C1q reduced adsorption of DENV-1/4G2 and exerted a dual inhibitory effect on adsorption and internalization of DENV-1/2H2. Distinct endocytic pathways in the presence of antibody corresponded to conditions where C1q produced a differential action. Also, C1q did not affect the intrinsic cell response mediated by FcγR in human myeloid cells. The modulation of ADE of DENV-1 by C1q is dependent on the FcγR expressed on immune cells and the specificity of the antibody comprising the immune complex. Understanding protective and pathogenic mechanisms in the humoral response to DENV infections is crucial for the successful design of antivirals and vaccines.

The first dengue "endgame" summit was held in Syracuse, NY over August 9 and 10, 2023. Organized and hosted by the Institute for Global Health and Translational Sciences at SUNY Upstate Medical University, the gathering brought together researchers, clinicians, drug and vaccine developers, government officials, and other key stakeholders in the dengue field for a highly collaborative and discussion-oriented event. The objective of the gathering was to discuss the current state of dengue around the world, what dengue "control" might look like, and what a potential roadmap might look like to achieve functional dengue control. Over the course of 7 sessions, speakers with a diverse array of expertise highlighted both current and historic challenges associated with dengue control, the state of dengue countermeasure development and deployment, as well as fundamental virologic, immunologic, and medical barriers to achieving dengue control. While sustained eradication of dengue was considered challenging, attendees were optimistic that significant reduction in the burden of dengue can be achieved by integration of vector control with effective application of therapeutics and vaccines.

DENV infection outcomes depend on the host's variable expression of immune receptors and mediators, leading to either resolution or exacerbation. While the NS3 protein is known to induce robust immune responses, the specific impact of its protease region epitopes remains unclear. This study investigated the effect of recombinant NS3 protease region proteins from all four DENV serotypes on splenocyte activation in BALB/c mice (n = 5/group). Mice were immunized with each protein, and their splenocytes were subsequently stimulated with homologous antigens. We measured the expression of costimulatory molecules (CD28, CD80, CD86, CD152) by flow cytometry, along with IL-2 production, CD25 expression, and examined the antigen-specific activation of CD4 + and CD8 + T cells. Additionally, the expression of IL-1, IL-10, and TGF-β1 in splenocytes from immunized animals was assessed. Apoptosis was evaluated using Annexin V/PI staining and DNA fragmentation analysis. Stimulation of splenocytes from immunized mice triggered apoptosis (phosphatidylserine exposure and caspase 3/7 activation) and increased costimulatory molecule expression, particularly CD152. Low IL-2 production and low CD25 expression, as well as sustained expression of the IL-10 gene. These results suggest that these molecules might be involved in mechanisms by which the NS3 protein contributes to viral persistence and disease pathogenesis.

There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified CXCR3-antagonist from our compound library, namely 7D, which inhibited all serotypes of DENV in vitro. With a half-life of ~2.85 h in plasma and no significant toxicity, 7D supplementation (8 mg/kg-body-weight) to DENV2-infected IFNα/β/γR-/-AG129 or wild-type C57BL6 mice increased synthesis of IFN-α/β and IFN-λ, and rescued disease symptoms like thrombocytopenia, leukopenia and vascular-leakage, with improved survival. 7D, having the property to inhibit Sirt-1 deacetylase, promoted acetylation and phosphorylation of STAT3, which in-turn increased plasmablast proliferation, germinal-center maturation and synthesis of neutralizing-antibodies against DENV2 in mice. A STAT3-inhibitor successfully inhibited these effects of 7D. Together, these observations identify compound 7D as a stimulator of IFN-α/β/λ synthesis via CXCL4:CXCR3:p38:IRF3 signaling, and a booster for neutralizing-antibody generation by promoting STAT3-acetylation in plasmablasts, capable of protecting dengue infection.

Dengue is a vector-borne debilitating disease that is manifested as mild dengue fever, dengue with warning signs, and severe dengue. Dengue infection provokes a collective immune response; in particular, the innate immune response plays a key role in primary infection and adaptive immunity during secondary infection. In this review, we comprehensively walk through the various markers of immune response against dengue pathogenesis and outcome.

Innate immune response against dengue involves a collective response through the expression of proinflammatory cytokines, such as tumor necrosis factors (TNFs), interferons (IFNs), and interleukins (ILs), in addition to anti-inflammatory cytokines and toll-like receptors (TLRs) in modulating viral pathogenesis. Monocytes, dendritic cells (DCs), and mast cells are the primary innate immune cells initially infected by DENV. Such immune cells modulate the expression of various markers, which can influence disease severity by aiding virus entry and proinflammatory responses. Adaptive immune response is mainly aided by B and T lymphocytes, which stimulate the formation of germinal centers for plasmablast development and antibody production. Such antibodies are serotype-dependent and can aid in virus entry during secondary infection, mediated through a different serotype, such as in antibody-dependent enhancement (ADE), leading to DENV severity. The entire immunological repertoire is exhibited differently depending on the immune status of the individual.

Dengue fever through severe dengue proceeds along with the modulated expression of several immune markers. In particular, TLR2, TNF-α, IFN-I, IL-6, IL-8, IL-17 and IL-10, in addition to intermediate monocytes (CD14+CD16+) and Th17 (CD4+IL-17+) cells are highly expressed during severe dengue. Such markers could assist greatly in severity assessment, prompt diagnosis, and treatment.

Dengue virus, an arbovirus of genus Flavivirus, is an infectious disease causing organisms in the tropical environment leading to numerous deaths every year. No therapeutic is available against the virus till date with only symptomatic relief available. Here, we have tried to design therapeutic compounds from scratch by fragment based method followed by pharmacophore based modelling to find suitable similar structure molecules and validated the same by MD simulation, followed by binding energy calculations and ADMET analysis. The receptor binding region of the dengue envelope protein was considered as the target for prevention of viral host cell entry and thus infection. This resulted in the final selection of kanamycin as a stable binding molecule against the Dengue virus envelope protein receptor binding domain. This study results in selection of a single molecule having high binding energy and prominent stable interactions as determined by post simulation analyses. This study aims to provide a direction for development of small molecule therapeutics against the dengue virus in order to control infection. This study may open a new avenue in the arena of structure based and fragment based therapeutic design to obtain novel molecules with therapeutic potential.

The online version contains supplementary material available at 10.1007/s40203-024-00262-9.

In tropical and subtropical regions, dengue fever is a common febrile illness that is mostly spread by Aedes mosquitoes. Urban population migration, inadequate water storage facilities, and high mosquito density are features associated with this disease. The severity of the illness ranges from mild to deadly dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), often with severe cases causing profound shock from extensive plasma leakage, and may result in demise. The symptoms of the illness include headache, myalgia, retro-orbital pain, and hemorrhagic signs. There may also be an intermittent shift in blood vessel integrity and coagulation, but recovery is typically complete and rapid. In this review, we emphasize the immunological aspects of this illness. The intricate interactions among the virus, host genes, and host immune systems impact the pathophysiology of dengue. Postinfection antibody-dependent enhancement is prominent, which significantly influences the etiology and virulence of the disease. Whereas the severe form only manifests when the host immune system is actively working to eradicate the infection by secreting several inflammatory cytokines, chemokines, and lipid mediators, for example, early dengue virus infection (DVI) resulted in the production of Interleukin 2 (IL-2), IL-6, and later infection, IL-4, IL-5, and IL-10. Higher concentrations of interferons gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor (MIF), IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-13 were found in DHF patients. These are significantly more prevalent in severe infections than in mild ones. Numerous immunopathogenic processes involving both virus and host variables influence the severity of dengue. There is growing evidence that a compromised immune system limits viral clearance and causes severe inflammation, which in turn causes dengue hemorrhagic fever and dengue shock syndrome. Furthermore, the capacity of DENV to infect a broad range of immune cells, such as macrophages, dendritic cells, mast cells, T and B cells, and monocytes, further dysregulates these cells' antiviral activities, leading to the spread of the virus. Even though a number of risk factors linked to the advancement of the disease have been suggested, further research and evaluation of novel technologies are necessary to understand the complicated etiology and develop reliable and effective vaccines to fight against this febrile illness.

Vascular endothelial growth factor (VEGF) is one of the proteins involved in dengue immunopathogenesis. It is overexpressed in severe dengue and contributes to vascular permeability and plasma leakage. In this study, we investigated the effects of VEGF and anti-VEGF treatments on endothelial cells in vitro, to assess the potential use of anti-VEGF antibodies in managing severe dengue.

Human pulmonary microvascular endothelial cells were treated with VEGF and a VEGF/anti-VEGF combination. The effects of the treatments were studied using an endothelial permeability assay and microarray gene expression profiling. In the permeability assay, the fluorescein isothiocyanate (FITC)-dextran fluorescence signal across the endothelial monolayer was recorded, and the cells were stained with PECAM-1 to detect gap formation. RNA was extracted from treated cells for microarray gene profiling and analysis. The results were analyzed for differentially expressed genes (DEGs) and gene enrichment analysis. The DEGs were subjected to STRING to construct the protein-protein interaction network and then Cytoscape to identify the hub genes.

VEGF-treated endothelial cells showed greater movement of FITC-dextran across the monolayer than VEGF/anti-VEGF-treated cells. There were 111 DEGs for VEGF-treated cells and 118 DEGs for VEGF/anti-VEGF-treated cells. The genes upregulated in VEGF-treated cells were enriched in inflammatory responses and regulation of the endothelial barrier, nitric oxide synthesis, angiogenesis, and the nucleotide-binding oligomerization domain-like receptor signaling pathway. Top 10 hub genes were identified from the DEGs.

VEGF treatment increased permeability across endothelial cells, while anti-VEGF reduced this leakage. Analysis of VEGF-treated endothelial cells identified hub genes implicated in severe dengue. The top 10 hub genes were TNF, IL1B, IL6, CCL2, PTGS2, ICAM1, CXCL2, CXCL1, CSF2, and TLR2. The results of this study show that using anti-VEGF antibodies to neutralize VEGF may be a promising therapy to prevent the progression of dengue to severe dengue.

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 pan-serotype 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.

In recent decades, increases in temperature and tropical rainfall have facilitated the spread of mosquito species into temperate zones. Mosquitoes are vectors for many viruses, including West Nile virus (WNV) and dengue virus (DENV), and pose a serious threat to public health. This review covers most of the current knowledge on the mosquito species associated with the transmission of WNV and DENV and their geographical distribution and discusses the main vertebrate hosts involved in the cycles of WNV or DENV. It also describes virological and pathogenic aspects of WNV or DENV infection, including emerging concepts linking WNV and DENV to the reproductive system. Furthermore, it provides an epidemiological analysis of the human cases of WNV and DENV reported in Europe, from 1 January 2018 to 31 December 2023, with a particular focus on Italy. The first autochthonous cases of DENV infection, with the most likely vector being Aedes albopictus, have been observed in several European countries in recent years, with a high incidence in Italy in 2023. The lack of treatments and effective vaccines is a serious challenge. Currently, the primary strategy to prevent the spread of WNV and DENV infections in humans remains to limit the spread of mosquitoes.

Dengue virus (DENV), transmitted by infected mosquitoes, is a major public health concern, with approximately half the world's population at risk for infection. Recent decades have increasing incidence of dengue-associated disease alongside growing frequency of outbreaks. Although promising progress has been made in anti-DENV immunizations, post-infection treatment remains limited to non-specific supportive treatments. Development of antiviral therapeutics is thus required to limit DENV dissemination in humans and to help control the severity of outbreaks. Dendritic cells (DCs) are amongst the first cells to encounter DENV upon injection into the human skin mucosa, and thereafter promote systemic viral dissemination to additional human target cells. Autophagy is a vesicle trafficking pathway involving the formation of cytosolic autophagosomes, and recent reports have highlighted the extensive manipulation of autophagy by flaviviruses, including DENV, for viral replication. However, the temporal profiling and function of autophagy activity in DENV infection and transmission by human primary DCs remains poorly understood. Herein, we demonstrate that mechanisms of autophagosome formation and extracellular vesicle (EV) release have a pro-viral role in DC-mediated DENV transmission. We show that DENV exploits early-stage canonical autophagy to establish infection in primary human DCs. DENV replication enhanced autophagosome formation in primary human DCs, and intrinsically-heightened autophagosome biogenesis correlated with relatively higher rates of DC susceptibility to DENV. Furthermore, our data suggest that viral replication intermediates co-localize with autophagosomes, while productive DENV infection introduces a block at the late degradative stages of autophagy in infected DCs but not in uninfected bystander cells. Notably, we identify for the first time that approximately one-fourth of DC-derived CD9/CD81/CD63+ EVs co-express canonical autophagy marker LC3, and demonstrate that DC-derived EV populations are an alternative, cell-free mechanism by which DCs promote DENV transmission to additional target sites. Taken together, our study highlights intersections between autophagy and secretory pathways during viral infection, and puts forward autophagosome accumulation and viral RNA-laden EVs as host determinants of DC-mediated DENV infection in humans. Host-directed therapeutics targeting autophagy and exocytosis pathways thus have potential to enhance DC-driven resistance to DENV acquisition and thereby limit viral dissemination by initial human target cells following mosquito-to-human transmission of DENV.

Guangzhou has been the city most affected by the dengue virus (DENV) in China, with a predominance of DENV serotype 1 (DENV-1). Viral factors such as dengue serotype and genotype are associated with severe dengue (SD). However, none of the studies have investigated the relationship between DENV-1 genotypes and SD. To understand the association between DENV-1 genotypes and SD, the clinical manifestations of patients infected with different genotypes were investigated. A total of 122 patients with confirmed DENV-1 genotype infection were recruited for this study. The clinical manifestations, laboratory tests, and levels of inflammatory mediator factors were statistically analyzed to investigate the characteristics of clinical manifestations and immune response on the DENV-1 genotype. In the case of DENV-1 infection, the incidence of SD with genotype V infection was significantly higher than that with genotype I infection. Meanwhile, patients infected with genotype V were more common in ostealgia and bleeding significantly. In addition, levels of inflammatory mediator factors including IFN-γ, TNF-α, IL-10, and soluble vascular cell adhesion molecule 1 were higher in patients with SD infected with genotype V. Meanwhile, the concentrations of regulated upon activation normal T-cell expressed and secreted and growth-related gene alpha were lower in patients with SD infected with genotype V. The higher incidence of SD in patients infected with DENV-1 genotype V may be attributed to elevated cytokines and adhesion molecules, along with decreased chemokines.

Dengue cases can progress to severe ant life-threating forms particularly in subsequent heterologous infections. However, recent studies had explored additional risk factors, including underlying health conditions, even in individuals without prior exposure to dengue, notably, in patients with endothelial dysfunction and chronic inflammation. This study examines the link between diabetes and the development of severe dengue disease in dengue-naive patients during the 2019 dengue outbreak in São Jose do Rio Preto, Brazil.

We enrolled 529 laboratory-confirmed dengue cases, identified through DENV RT-PCR or NS1 antigen assays in a hospital cohort of acute febrile illness. Subsequently, we investigated the presence of anti-dengue and anti-Zika IgG antibodies. Samples testing positive for Zika were excluded from the analyses. Two groups were analyzed: naïve (DV-), and dengue history (DV+).

Initially, presence of diabetes and kidney disease, as well as being dengue-naive, were associated with a higher frequency of severe and potentially severe clinical outcomes. Multivariate analysis identified diabetes as a risk factor, while the presence of anti-dengue antibodies was considered protective. Analysis of dengue naïve samples, highlighted diabetes as an independent risk factor to severe forms of dengue disease. In DV+ patients, no condition was highlighted as a risk factor by univariate analysis or multivariate analysis.

We investigated and confirmed diabetes as a risk factor for severe dengue disease in individuals without prior dengue or Zika exposure. Our conclusions raise significant concerns given diabetes' ever increasing global prevalence and its potential impact on patients with or previous dengue exposure.

Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether the antigenic distances between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalizations across years. Here, we develop a framework that combines detailed antigenic and genetic characterization of viruses with details on hospitalized cases from 21 years of dengue surveillance in Bangkok, Thailand, to identify the role of the antigenic profile of circulating viruses in determining disease risk. We found that the risk of hospitalization depended on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximized at intermediate antigenic distances. These findings suggest that immune imprinting helps determine dengue disease risk and provide a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions of people contract the virus through bites from infected female mosquitoes of the Aedes species. In the majority of individuals, the infection is asymptomatic, and the immune system successfully manages to control virus replication within a few days. Symptomatic individuals may present with a mild fever (Dengue fever or DF) that may or may not progress to a more critical disease termed Dengue hemorrhagic fever (DHF) or the fatal Dengue shock syndrome (DSS). In the absence of a universally accepted prophylactic vaccine or therapeutic drug, treatment is mostly restricted to supportive measures. Similar to many other viruses that induce acute illness, DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. To search for new therapeutic options, understanding the underlying host-virus regulatory system involved in various biological processes of the viral life cycle is essential. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation.