Dengue: how to explain the manifestation of severe forms?

By Fatéma Dodat

Source Image : Pixabay

With 55% of the world's population now exposed to dengue fever, this virus has now spread its territory of infection beyond tropical and subtropical regions. Although it is often mild, this viral infection manifests itself in a severe and unpredictable way in more than 500,000 people each year. Different hypotheses have been suggested to explain the severity of these symptoms. Back on dengue and these lines of research.

The virus

Dengue is spread between humans through an infected mosquito. During a bite, the mosquito picks up the virus from an infected person and can transmit it to a healthy person. This mosquito, belonging to the Aedes genus, has an incubation period of 4 to 10 days, and can then transmit the virus for the rest of its life. Four dengue serotypes exist (DENV-1, -2, -3, -4) depending on the immune responses the virus causes when it infects the body. This diversity is explained by the 30% difference observed in the letters that make up the viral molecule.

Different responses depending on the serotypes

Although often mild, with the manifestation of high fever, headache, and muscle or joint pain, viral infection can cause more severe symptoms and lead to 25,000 deaths a year. One of the hypotheses put forward by the researchers to explain this severity is that certain dengue serotypes are more dangerous than others. Indeed, a study conducted between 1995 and 2002 compared the serological and viral load rates of 2,715 patients with severe symptoms associated with dengue. A first infection with DENV-1 or DEN-3 seems to generate a more severe clinical manifestation compared to the other serotypes. Furthermore, another study notes that the body's immune response differs when faced with each serotype. If the serotypes DENV-2 and DENV-3 induce a greater total response of cytokines, which are the inflammatory molecules resulting from the immune response, DENV-4 seems to be the one that demands the least to immunity.

A second riskier infection

Another hypothesis suggested regarding the severity of the symptoms is that the patient may have been infected a second time with a different strain of the virus. Indeed, a first infection offers lasting protection to the individual against this strain. However, if the patient is subsequently infected with a different serotype, this second infection could be more dangerous. The initial infection allows the body to develop specific antibodies against the viral serotype that infected the individual. These antibodies, which are the virus's detection and neutralization agents, confer lasting immunity against this serotype. However, it is very short towards the other serotypes which did not infect the patient. Meta-analyzes, aimed at evaluating this immune window, estimate that a second infection which occurs 1.6 and 2.6 years after the first infection, could be responsible - respectively - for the manifestation of severe clinical symptoms and hemorrhagic fevers. When infected a second time with a different dengue serotype, antibodies are sometimes unable to neutralize the virus. Howver, they form complexes with it. These complexes have a higher affinity for the Fcγ receptor, which constitutes the lock that the virus opens in order to enter the cell. This receptor is located on the surface of different cells, including certain white blood cells, which facilitates the entry of the virus into these cells and allows it to replicate. This theory, called “facilitation of antibody infection” (Antibody-dependent enhancement) has been demonstrated in animals for the dengue virus and it is also suspected in the case of other viruses such as HIV. For the moment, the association of severe symptoms during a third or fourth infection is considered, respectively, as rare or non-existent (here and here).

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