Introduction
Dengue is a viral illness caused by the dengue virus (DENV), which has four distinct serotypes (DENV-1 to DENV-4). It is often called "break-bone fever" due to severe muscle and joint pain. Symptoms include high fever, headache, rash, and pain behind the eyes. While most cases are mild or asymptomatic, severe forms (dengue hemorrhagic fever or dengue shock syndrome) can lead to plasma leakage, organ failure, or death. Dengue is primarily transmitted through the bite of infected Aedes mosquitoes, which become carriers after biting an infected person. These mosquitoes are most active during the day, and transmission can also rarely occur through blood products, organ donation, or from mother to child. Infection is most prevalent in urban areas with stagnant water and poor sanitation located in tropical and subtropical climates.
About DENV
Dengue virus (DENV) belongs to the family of Flaviviridae genus of Flavivirus, and is an enveloped, positive-sense single-stranded RNA. This means that DENV can immediately commence translation upon hijacking of host cells. Infection is caused by four different serotypes of Dengue virus, namely: DENV-1, DENV-2, DENV-3, DENV-4. These serotypes are closely related, but each interacts differently with the antibodies in human blood serum.
Genome structure of dengue virus (Guzman et al., 2010)
DENV genome consists of a single open reading frame (ORF) flaked by 5’ and 3’ untranslated regions (UTRs) and also encodes ten genes which consist of non-structural proteins (NS) and structural proteins (Capsule (C), membrane (M), and envelope (E)). Structural proteins form the physical structure of the dengue virus particle (virion) and are essential for its assembly, entry into host cells, and maturation. Non-structural proteins, on the other hand, are not part of the virion structure but are critical for viral replication, polyprotein processing, and evasion of host immune responses.
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Structural Proteins:
- Capsid (C): Forms the nucleocapsid, protecting the viral RNA and aiding in virion assembly.
- Membrane (M): Derived from the precursor prM, it facilitates virus maturation and assembly.
- Envelope (E): Mediates host cell attachment and entry, serving as the primary target for neutralizing antibodies.
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Structural Proteins:
- NS1: Supports viral replication and immune evasion; secreted as a hexamer, it is a diagnostic marker.
- NS2A: Anchors replication complexes to membranes and coordinates virion assembly.
- NS2B: Acts as a cofactor for NS3 protease, enabling polyprotein cleavage.
- NS3: A multifunctional enzyme with protease, helicase, and NTPase activities, essential for replication and polyprotein processing.
- NS4A: Induces membrane rearrangements to form replication compartments.
- NS4B: Enhances replication and inhibits interferon signaling.
- NS5: The largest protein, with RNA-dependent RNA polymerase and methyltransferase activities, crucial for RNA synthesis and capping.
DENV replication
DENV enters host cells (e.g., monocytes, macrophages) via receptor-mediated endocytosis, facilitated by the E protein binding to receptors like DC-SIGN. In the acidic endosome, the E protein triggers membrane fusion, releasing the RNA genome into the cytoplasm. The genome is translated into a polyprotein, processed by proteases, and replicated in endoplasmic reticulum-derived membrane vesicles. New virions assemble and exit via the Golgi, undergoing maturation to become infectious.
Conformational changes in DENV
DENV takes two structures, the immature (non-infectious) conformation and the mature (infectious) form.
The immature conformation is assembled in the endoplasmic reticulum; immature virions have a spiky surface due to 60 trimeric spikes of prM-E heterodimers. The prM protein covers the E protein’s fusion loop, preventing premature fusion with host membranes, rendering the virion non-infectious. This structure protects the virus during assembly and transport within the host cell.
In the trans-Golgi network, the host enzyme furin cleaves prM, releasing the “pr” peptide and leaving the M protein. This cleavage allows the E protein to form 90 homodimers in a smooth, herringbone pattern, exposing the fusion loop. The mature virion can bind host receptors and fuse with endosomal membranes, enabling RNA release and infection. Cryo-electron microscopy studies reveal these structural differences, with mature virions optimized for infectivity.
Why do some get severe dengue infection?
As previously stated, there are four serotypes of the dengue virus: DENV-1, DENV-2, DENV-3, and DENV-4. An initial infection with one serotype usually results in only modest, transient protection against other serotypes but lifetime immunity to that serotype. However, because of antibody-dependent enhancement (ADE), a secondary infection with a different serotype considerably raises the likelihood of developing severe dengue. Pre-existing antibodies from the initial infection attach to the novel serotype in ADE, but they are unable to neutralize it. Rather, through Fc receptors, these antibodies facilitate viral entrance into immune cells (like monocytes), increasing viral loads and the immunological response, which can cause serious symptoms including bleeding and vascular leakage.
Dengue cases globally and in Singapore
As of May 2025, WHO reported approximately 2,532,929 dengue cases globally, with 1,305 related fatalities, with the Americas, Southeast Asia, and the Western Pacific being the most affected regions. The Americas alone reported over 2 million cases by April 2025, surpassing the 2023 high of 4.6 million. In 2024, a record 13 million cases were reported, driven by climate change, urbanization, and El Niño effects.
In Singapore, NEA reports indicate around 1,900 dengue cases based on cumulative data up to epidemiological week 21, and a weekly average of about 100 cases.
How is Dengue virus diagnosed?
- Virus antigen detection – detection of NS1 protein secreted into blood during infection
- Antibody tests (IgM and IgG) – IgM is produced during primary infection while IgG is produced when there is a secondary infection
- Polymerase chain reaction (PCR) – determines the amount of DENV RNA in blood, serum, or plasma
Vaccination and precautions
The only available and approved vaccine for Dengue virus in Singapore is Dengvaxia (Dengue Fever, n.d.). Precautions should be taken to mitigate the spread of DENV:
- Staying in rooms that have air conditioning
- Wearing long, covered clothing
- Constantly applying an insect repellent
Dengue remains a formidable public health challenge, exacerbated by urbanization, climate change, and viral evolution. Understanding its molecular biology and immunopathology is critical for developing targeted interventions. In endemic regions like Singapore, integrated strategies—combining surveillance, vector control, and community engagement—are vital to curbing transmission and preventing severe outcomes.
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References
Guzman, M. G., Halstead, S. B., Artsob, H., Buchy, P., Farrar, J., Gubler, D. J., Hunsperger, E., Kroeger, A., Margolis, H. S., Martínez, E., Nathan, M. B., Pelegrino, J. L., Simmons, C., Yoksan, S., & Peeling, R. W. (2010). Dengue: a continuing global threat. Nature Reviews Microbiology , 8 (S12), S7–S16. https://doi.org/10.1038/nrmicro2460
Da Silva, P. G., Reis, J. a. S. D., Rodrigues, M. N., Da Silva Ardaya, Q., & Mesquita, J. R. (2023). Serological Cross-Reactivity in zoonotic flaviviral infections of medical Importance. Antibodies , 12 (1), 18. https://doi.org/10.3390/antib12010018
Global dengue surveillance . (n.d.). https://worldhealthorg.shinyapps.io/dengue_global/
Dengue cases . (n.d.). https://www.nea.gov.sg/dengue-zika/dengue/dengue-cases
Dengue fever . (n.d.). Communicable Diseases Agency. https://www.cda.gov.sg/professionals/diseases/dengue-fever#ea54c488a1fa9492d386e7fbd793bfc7