Dengue

Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Five serotypes of the virus have been found, all of which can cause the full spectrum of disease. Nevertheless, scientists' understanding of dengue virus may be simplistic, as rather than distinct antigenic groups, a continuum appears to exist. This same study identified 47 strains of dengue virus. Additionally, coinfection with and lack of rapid tests for zika virus and chikungunya complicate matters in real-world infections.

Dengue virus has increased dramatically within the last 20 years, becoming one of the worst mosquito-borne human pathogens with which tropical countries have to deal. Current estimates indicate that as many as 390 million infections occur each year, and many dengue infections are increasingly understood to be asymptomatic or subclinical.

Based on the analysis of the envelope protein, at least three genotypes (1 to 3) are known. In 2013, a fourth serotype was reported. The rate of nucleotide substitution for this virus has been estimated to be 6.5×10−4 per nucleotide per year, a rate similar to other RNA viruses. The American African genotype has been estimated to have evolved between 1907 and 1949. This period includes World War I and World War II, which were associated with considerable movement of populations and environmental disturbance, factors known to promote the evolution of new vector-borne viral species.

A Bayesian analysis of all four serotypes estimated that their most recent common ancestor existed about 340 AD (95% confidence interval: 280 BC-850 AD).

Until a few hundred years ago, dengue virus was transmitted in sylvatic cycles in Africa, Southeast Asia and South Asia between mosquitoes of the genus Aedes and nonhuman primates, with rare emergences into human populations. The global spread of dengue virus, however, has followed its emergence from sylvatic cycles and the primary lifecycle now exclusively involves transmission between humans and Aedes mosquitoes. Vertical transmission from mosquito to mosquito has also been observed in some vector species. Dogs have been found to be infected by the virus, but more research is needed to determine if dogs or other animals can serve as reservoirs or are just incidental hosts.


Recent findings suggest that as the virus infects human cells, host homeostatic processes such as autophagy and ER stress response, not to mention apoptosis, are triggered depending on the infected cell type. The activation of autophagy and ER stress during infection enhances virus reproduction. Attempts to provide detailed summaries of the life cycle of dengue at the cellular level are published in review articles from different research groups.


The DENV genome is about 11000 bases of positive-sense, single stranded RNA (ssRNA) that codes for three structural proteins (capsid protein C, membrane protein M, envelope protein E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). It also includes short noncoding regions on both the 5' and 3' ends.


Common names for dengue fever include breakbone fever, vomiting and dandy fever; dengue hemorrhagic fever and dengue shock syndrome are the severe forms. Dengue is found in tropical and subtropical climates worldwide, mostly in urban and semiurban areas. People of all ages who are exposed to infected mosquitoes are possible victims of dengue fever. The disease occurs most often during the rainy season in tropical countries in Southeast Asia, South Asia and South America, with high numbers of infected mosquitoes. The virus is transmitted to humans through the bites of infected female mosquitoes, though humans are not capable of transmitting the disease and are not contagious. The incubation period is 3 to 14 days, while the period of the illness is 3–7 days. Signs and symptoms may include severe headache; retro-orbital pain; muscle, joint, and bone pain; macular or maculopapular rash; and minor hemorrhagic manifestations, including petechiae, ecchymosis, purpura, epistaxis, bleeding gums, hematuria, or a positive tourniquet test result. A recent systematic review and meta-analysis showed that allergic symptoms are one of the core symptoms that are highly associated with dengue severity.

In recent years, many studies have shown that flaviviruses, especially dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response.

Only one vaccine for dengue is currently approved in 11 countries (Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore). Several vaccines are under development by private and public researchers. Developing a vaccine against the disease is challenging. With four different serotypes of the virus that can cause the disease, the vaccine must immunize against all four types to be effective. Vaccination against only one serotype could possibly lead to severe dengue hemorrhagic shock when infected with another serotype due to antibody-dependent enhancement. When infected with dengue virus, the immune system produces cross-reactive antibodies that provide immunity to that particular serotype. However, these antibodies are incapable of neutralizing other serotypes upon reinfection and actually increase viral replication. When macrophages consume the ‘neutralized’ virus, the virus is able to replicate within the macrophage, causing disease. These cross-reactive, ineffective antibodies ease access of virus into macrophages, which induces more severe disease (dengue hemorrhagic fever, dengue shock syndrome). A common problem faced in dengue-endemic regions is when mothers become infected with dengue; after giving birth, offspring carry the immunity from their mother and are susceptible to hemorrhagic fever if infected with any of the other three serotypes. One vaccine was in phase III trials in 2012 and planning for vaccine usage and effectiveness surveillance had started.
There are no approved direct antiviral treatments for Dengue fever. Most antiviral drug research for Dengue infections has focussed on inhibition of the NS2B/NS3 protease or NS5 proteins. One drug, Balapiravir, a repurposed hepatitis C NS5 polymerase inhibitor progressed to a Phase II clinical trial before being stopped due to lack of efficacy.