Dengue, an arthropod-borne viral disease has recently grown in importance as a health issue in Asia. It is the root cause of more than 70% of all common ailments. The dengue virus (DENV) is part of the Flavivirus genus within the Flaviviridae family, which comprises over 70 significant pathogens that cause diseases in humans, primarily affecting the intertropical areas. This viral infection is spread to people through the bite of female mosquitoes, predominantly from the Aedes aegypti species, with Aedes albopictus serving as a secondary vector.¹

In recent years, the worldwide occurrence of dengue has escalated, marking it as the most rapidly dispersing insect vector-borne disease (VBD).² An epidemiological assessment reveals that DENV infection reaches about two-fifths of the global population, affecting nearly 390 million individuals yearly. The countries most affected by dengue are Brazil, Argentina, and Mexico. Based on the WHO Global Dengue Surveillance, between January and November 2024, the overall dengue case count reached 13,860,025, alongside a total of 9990 fatalities. Most of these instances originated from the Americas, which recorded 12,669,716 cases and 7713 deaths. The region with the second-highest impact was Southeast Asia, with an aggregate of 693,596 cases and 2002 deaths. Between January 2025 to March 2025, a total of 1,654,640 cases were reported, out of which 603,148 were confirmed cases, 4154 severe cases and 852 deaths were reported. It is important to note that numerous dengue cases are asymptomatic or mild, and some instances might have been incorrectly diagnosed as other febrile illnesses, suggesting that the actual incidence might surpass reported figures.^2,3 Furthermore, urban growth and population shifts have significantly contributed to the rising burden in the area.⁴ As per the report released by The National Centre for Vector Borne Diseases Control (NCVBDC), Government of India, in 2019, there were 157,315 reported cases with 166 fatalities, and in 2024, up to February, 233,400 cases were noted with 236 deaths.⁵ Figure 1 illustrates the total number of reported dengue cases across different countries, from January 2024 to May 2025, with a color gradient indicating the burden from low (light yellow) to extremely high (dark red). According to the WHO data on global dengue situation, a total of 17,710,747 cases and 12,887 deaths were reported.³  India reported over 232,425 total cases with 200,334 confirmed and 233 deaths.

The highest number of cases are reported during the monsoon season, which typically runs from June to September. Dengue is endemic in many parts of India, and outbreaks have occurred in various states, including Delhi, Maharashtra, Tamil Nadu, Karnataka, West Bengal, Rajasthan, Punjab and Kerala (Figure 2). The disease is more common in urban areas, where the mosquito vector breeds in stagnant water and can easily spread the virus from person to person.

Joint discomfort, rashes, headache, low white blood cell count, moderate asymptomatic dengue fever (DF), severe dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS) are all symptoms of dengue virus infection. Within 3-14 days of infection, a dengue symptom will appear. Blood pressure drops, blood platelet levels drop, and bleeding all occur as a result of a serious dengue hemorrhagic fever.⁶ All age groups of people, including infants, toddlers, and adults, are susceptible to the flu-like illness known as dengue fever, although pregnant women and those with weakened immune systems are particularly at risk. Therefore, mortality may be reduced and people could be made aware of this disease.⁷

Structure, function, replication and transmission of the virus
Structure and function
The dengue virus genome consists of a single strand of RNA. This RNA is classified as positive sense because it can be directly translated into proteins. The viral genome contains ten genes. The genome is translated into one long polypeptide which is then cleaved into ten proteins. Three of these proteins are structural: the capsid (C), envelope (E), and membrane (M) proteins (Figure 3). The remaining seven are non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 (Figure 4). These non-structural proteins are involved in the processes of viral replication and assembly. The dengue virus has a spherical shape and with a size of about 50 nm. Nucleocapsid is the core of the virus, which consists of the viral genome along with C proteins. Encasing the nucleocapsid is a membrane known as the viral envelope, which is a lipid bilayer acquired from the host. Within the viral envelope are 180 copies of the E and M proteins that traverse the lipid bilayer. These proteins create a protective external layer that regulates the entry of the virus into human cells.^8,9

Serotypes and replication
Dengue is caused by four related viruses identified as DENV-1, DENV-2, DENV-3, and DENV-4. These are known as serotypes since they interact differently with antibodies in human blood serum. Although the dengue viruses are alike, sharing around 65% of their genetic makeup, there is still some genetic diversity within each serotype. Regardless of these differences, contracting any of the dengue serotypes leads to the same disease and set of clinical symptoms.^8,10 The DENV-2 serotype is notorious for being more lethal than other serotypes.

A cell becomes infected when a virus attaches to the host cell’s surface.^11,12 Through receptor-mediated endocytosis, in which the cell membrane creates an endosome, it enters the cell. In order to provide a port for the genetic material to release, the virus penetrates the endosome deeply and waits for the membrane to become negatively charged. Now, the virus present in fluid of the cell starts to multiply. Changes in the pH of the secretory channel during its passage have a significant impact on the virus’s ability to develop. The endocytosis process allows the dengue virus to cling to a host cell’s surface and enter the cell.¹¹ The virus releases its contents into the cytoplasm after merging with the endosomal membrane deep inside the cell. As the virus particle breaks down, the viral genome is released. When the viral RNA (vRNA) is translated into a single polypeptide and then split into 10 proteins, the viral genome is replicated. On the surface of the endoplasmic reticulum (ER), viral assembly occurs when freshly produced RNA and structural proteins protrude. The mechanism via which the immature viral particles are transported is the trans-Golgi network (TGN), where the viral particles evolve and convert into their infectious condition. The mature viruses are subsequently expelled from the cell and can move on to other hosts (Figure 5).

Transmission of DENV
Aedes aegypti is a small, dark mosquito characterized by white lyre shaped patterns and striped legs. This mosquito primarily feeds on mammalian hosts, especially humans, even when other hosts are available. It also feeds several times throughout a single gonotrophic cycle (the cycle of feeding and egg production), which has consequences for the transmission of diseases.¹³ An egg takes 7-10 days to mature into an adult mosquito. Female Aedes mosquitoes lay eggs on the inner surfaces of water-holding containers. Larvae hatch from mosquito eggs and inhabit water. Larvae develop into pupae. Pupae evolve into adult, flying mosquitoes. Adult female mosquitoes bite humans and animals. Mosquitoes require blood to generate eggs¹⁴ (Figure 6).

The transmission of all four serotypes is maintained in two cycles: sylvatic (transmission among wild animals) and human. Both the cycles are ecologically and evolutionarily distinct. This is maintained by non-human primates or by a monkey-Aedes-monkey cycle in the sylvatic habitats of West Africa, Southeast Asia, peninsular Malaysia, and eastern Senegal. The incubation period of the DENV ranges from 3-14 days, averaging 4-7 days.^13,14

Pathogenesis of DENV infection
DENV pathogenesis involves a complex interplay between viral replication and host immune responses, leading to a wide spectrum of clinical outcomes. Transmission begins when an infected Aedes mosquito introduces the virus into the human host. The virus initially infects dendritic cells and subsequently spreads to macrophages, which serve as major sites for viral replication. During a primary infection, innate immune cells such as natural killer (NK) cells and macrophages play a crucial role in viral clearance. However, antibody-dependent enhancement (ADE) may occur, where non-neutralizing or suboptimal antibodies facilitate increased viral entry into Fc receptor–bearing cells, promoting higher viral loads and disease severity.^9,14

In cases of secondary infection with a different DENV serotype, memory T and B cells are rapidly activated. While this adaptive immune response aims to control viral replication, cross-reactive but non-protective antibodies can exacerbate ADE, leading to heightened viral dissemination and immune activation. The resulting immune response involves both innate and adaptive arms. Innate immunity, characterized by NK cell and macrophage activation, induces pro-inflammatory cytokines, contributing to fever and systemic manifestations. Concurrently, B cell activation produces antibodies, while T cells mediate cytotoxicity and cytokine release.^14,15

An exaggerated or dysregulated adaptive immune response is associated with increased vascular permeability and endothelial dysfunction, leading to hallmark clinical features such as rash and plasma leakage. Severe cases often progress to thrombocytopenia, a consequence of bone marrow suppression, immune-mediated platelet destruction, and increased peripheral consumption, which together heighten the risk of hemorrhage (Figure 7). Overall, DENV pathogenesis is a dynamic process shaped by viral factors and host immune responses, where ADE and immune dysregulation play pivotal roles in the progression from mild febrile illness to severe dengue.^14-16

Diagnostic modalities
Early and accurate diagnosis of DENV infection is crucial for prompt treatment, outbreak management, and lowering case fatality rates. Clinical/syndromic diagnosis, laboratory-based techniques, and novel, developing technologies are the main categories into which current diagnostic modalities are divided.⁹ The usefulness of each technique, which has its own advantages and disadvantages, is frequently contingent upon the stage of the infection, the resources available, and any cocirculating infections in endemic areas. Dengue is categorized by the WHO into three clinical categories: dengue without warning symptoms, dengue with warning signs, and severe dengue which includes DHF and DSS dengue shock syndrome. Signs and symptoms during and after the acute febrile phase serve as the basis for clinical evaluation.^9,17-19 New diagnostic platforms have been developed in response to the growing need for quick and easily available diagnostics, particularly in resource-constrained environments and during epidemics (Table 1).

Table (1):
Summary of Dengue Diagnostics modalities^9,17-19

Current therapeutic approaches and limitations
There is currently no designated antiviral therapy for dengue illness. The main goal is to alleviate pain symptoms. In most instances, dengue fever can be managed at home with pain relief medications. Hydration, pain relievers, and adequate rest are usually sufficient. Acetaminophen is commonly utilized for pain management. Non-steroidal anti-inflammatory medications such as ibuprofen and aspirin should be avoided, as they may heighten the risk of bleeding. It is essential to closely monitor severe cases of dengue.^9,20

Admission is necessary for individuals who have warning signs, have severe dengue fever, or are in other circumstances, such as being an infant, an older adult, pregnant, diabetic, or living alone. IV crystalloids may be started in patients with warning indications, and the fluid rate is adjusted according to the patient’s reaction. If the patient has already had prior boluses of crystalloid and has not responded, colloids are also the treatment of choice for individuals in shock. When the patient remains unstable and the hematocrit drops despite sufficient fluid resuscitation, a blood transfusion is necessary if there is significant bleeding or suspected bleeding. When the platelet count falls below 20,000 cells per microliter and the patient is at high risk of bleeding, platelet transfusion is considered.²¹

In spite of the high incidence and repeated outbreaks of dengue, there is now no particular antiviral therapy for the illness. Clinical management continues to be supportive, with an emphasis on hydration, symptom management, and careful observation of the course of the illness, particularly during the acute stage. The only licensed dengue vaccine, Dengvaxia, has shown limited efficacy and is associated with increased risk of severe disease in seronegative individuals, thereby restricting its widespread use.²² These therapeutic gaps emphasize the urgent need to investigate other approaches to dengue treatment. Due to their broad-spectrum antiviral properties, multi-target potential, and positive safety profiles, natural products, notably phytochemicals originating from medicinal plants, have become promising candidates in recent years. Numerous laboratory and computational studies have shown that certain plant compounds can disrupt critical phases of the dengue virus life cycle, such as how it enters cells, replicates, and processes proteins. This increasing evidence highlights the promise of plant-based compounds as a legitimate resource for creating new and safer treatments for dengue. For centuries, plants have been utilized across Asia, Africa, and Europe to address a range of illnesses, including those caused by viruses. Their antiviral characteristics are recognized for their ability to block viral replication, endocytosis, genome transcription, and protein production. Compounds found in plants may attach to surface proteins or to the biomembrane, DNA, or RNA of the virus.²³ A brief summary of approved and investigational vaccines approved for dengue has been mentioned below in Table 2.

Table (2):
Summary of approved and investigational dengue vaccines

Role of phytochemicals in antiviral therapy
Phytochemicals are bioactive substances that originate from plants. Their medicinal qualities have long been known, and their use in antiviral treatment has gained more scientific attention over the past two decades. Kadir et al. conducted a review of sixty-nine studies spanning from 1997-2012 that focused on plants with potential anti-dengue properties.²⁴ This review highlighted 31 different species from 24 families, including Ocimum sanctum, Carica papaya, Kaempferia parviflora, Phyllanthus urinaria, Piper retrofractum, and Psidium guajava, all noted for their effectiveness against dengue fever, as outlined in 61 studies. Out of these species, 11 yielded around 10 distinct phytochemicals. Some of these compounds include andrographolide, panduratin A, castanospermine, hydroxypanduratin A, carrageenans, turmerone, kappa carrageenan, galactomanan, and others that may hold promise for dengue fever treatment.²⁵

Natural medicines are effective against Ae. aegypti because of their antiviral, larvicidal, and mosquitocidal effects as well as their ability to repel mosquitoes.⁹ Numerous phytochemicals, including flavonoids, alkaloids, terpenoids, polyphenols, and saponins, have been shown to have potent inhibitory effects on DENV proteins, such as the E protein, the NS5 RNA dependent RNA polymerase, and the NS2B/NS3 protease. In vitro studies have validated the possibility of these substances lowering viral replication or cytopathic consequences in cell cultures, while in silico molecular docking investigations have revealed encouraging interactions between these compounds and viral targets.

Phytochemicals can disrupt different phases of the viral life cycle, such as viral attachment, penetration, replication, assembly, and release, thanks to their varied structures and mechanisms of action. The classes that have received the most attention include alkaloids, flavonoids, terpenoids, phenolics, polyphenols, lignans, and tannins. Several of these molecules have been shown to have broad-spectrum antiviral activity against both DNA and RNA viruses using in vitro, in vivo, and computational modeling techniques.^26,28

• Flavonoids including luteolin, quercetin, apigenin and baicalin have shown antiviral activity by blocking viral enzymes like reverse transcriptase, proteases, and RNA-dependent RNA polymerases. Quercetin, for instance, has been shown to be effective against dengue, influenza, and hepatitis viruses by preventing replication and altering the host’s immune response.^26,27,29
• Alkaloids like lycorine and berberine have shown notable antiviral effects, including against coronaviruses and flaviviruses, by blocking the production and translation of viral RNA.^26,29
• Terpenoids, such as glycyrrhizin and andrographolide, have immunomodulatory effects that lessen the severity of viral pathogenesis by preventing viral binding and replication.^28,29
• Phenolic compounds, including resveratrol, curcumin, and epigallocatechin gallate (EGCG), have been shown to reduce the production of pro-inflammatory cytokines and target diverse viral targets, making them useful in treating cellular inflammation caused by severe viral infections.^27,28
• It is known that tannins and lignans prevent infection of host cells by interfering with the viral proteins and thus inhibiting the integrity of the envelope.²⁷

In addition to having a direct impact on viruses, these chemicals also affect essential host pathways like NF-κB, MAPK, and interferon signaling, which are essential to the host’s immune response. They are appealing candidates for drug development due to their multitarget character, often reduced toxicity, and improved safety profiles.²⁸ Tables 3 and 4 displays the major medicinal plants available in India that have been reported against DENV infection. The extracts and the isolated phytocompounds from different plant species that have been shown to have anti-dengue property are described in the sections that follow Table 3. Classification of phytochemicals with reported anti-dengue activity and their mechanism of action.

Table (3):
Classification of phytochemicals with reported anti-dengue activity and their mechanism of action

Table (4):
Anti-dengue phytocompounds, mechanisms and experimental evidence^30,31

Quercetin, luteolin, apigenin, kaempferol, and other flavonoids have several antiviral effects, such as blocking the NS5 polymerase and decreasing cytokine release. Resveratrol, curcumin, EGCG, and other polyphenols have antioxidant and immunomodulatory effects that are helpful in treating dengue-related inflammation and endothelial leakage.³² Although mechanisms are not fully understood, crude extracts frequently have a wider serotype coverage and may operate by synergistic bioactive interactions. In silico screening is becoming more and more prevalent in forecasting phytocompound binding to conserved dengue viral proteins (NS2B/NS3, NS5, E), which speeds up the process of discovering new medications.³³