Dengue Fever

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Dengue is an infectious disease prevalent in over 120 countries and affects approximately 400 million people per year. Caused by the dengue virus (DENV), dengue results in a fever and may lead to death in extreme cases. Scientists have hotly debated why dengue virus affects patients more seriously during the second round of infection for many years and finally arrived at the conclusion: antibody-dependent enhancement. 

The dengue flavivirus is a single-stranded positive-sense RNA virus, meaning that the RNA genome can function as messenger RNA and be translated into protein as well. The dengue virus is comprised of three structural proteins — the capsid, precursor membrane, and envelope  — as well as seven non-structural proteins. The capsid has various functions; it protects the nucleic acid from digestion by enzymes and provides proteins that allow the virus to invade the host cell. The precursor membrane proteins play an important role in the maturation of flaviviruses, as the proteolytic cleavage of the precursor membrane protein leads to inert viruses turning infectious. The envelope proteins aid the assembly and release of the virus.

DENV can be transmitted in a variety of ways, with the most common method of transmission via mosquitoes, also known as arthropods. The infected Aedes species mosquitoes spread DENV as well as Zika through their bite. Furthermore, DENV can be passed on from a mother to their child. In addition, the sharing of blood can lead to the spreading of the dengue virus, albeit rarely. 

Photo: Dengue virus (DENV) micrograph.

Dengue has an incubation period of 4-10 days, with symptoms usually lasting from 2-7 days. The virus results in flu-like symptoms in patients: a high fever often accompanied by intense headaches, muscle pain, and nausea. Furthermore, in severe cases, patients may experience severe abdominal pain, frequent vomiting, fatigue, and rapid breathing. As a result of the accumulation of plasma and leaking of plasma, severe dengue is potentially fatal. 

The infection of the body with the dengue virus begins with DENV entering the bloodstream. This results in the infection of immature Langerhans cells, which are vital to the immune system as they normally detect foreign substances and then travel to the lymph node, triggering an immune response to protect the body. When an infected Langerhans cell has dengue viral antigens on its surface, monocytes and macrophages, two types of white blood cells crucial to fighting infection, are activated. Instead of phagocytosing the dengue virus, however, the monocytes and macrophages are infected by the virus; this leads to an amplification of the virus and it eventually spreads through the lymphatic system. 

At this point, although the initial response of the immune system has been foiled, additional defenses of the system aid in fighting the virus. The infected cells release interferons, a type of cytokine; these signaling proteins are made by the host cell in response to the presence of viruses and result in better detection of the infected cells. Additionally, interferons help activate both the innate and adaptive immune systems. The innate immune system is composed of cells and structures that offer nonspecific protection, while the adaptive immune system is able to identify specific pathogens. As a result of the activation of the adaptive immune system, B cells and T cells are able to join in and battle the pathogen. B-cells produce antibodies which recognize and neutralize the virus. T-cells, on the other hand, are able to kill the infected cells. The reaction of the immune system to the dengue virus eventually results in the body recovering from the dengue virus.

When a patient gets infected by a particular pathogen, memory T cells and memory B cells form a memory of the virus and help the immune system react quickly if the virus is detected again to suppress the pathogen. In the case of DENV, however, this does not hold true. Research has shown that getting the dengue virus for the second time can result in a more severe infection due to antibody-dependent enhancement, defined as when the binding of a virus to non-neutralizing antibodies results in the virus more easily entering host cells. When the body is infected with the dengue virus for the first time, both neutralizing and non-neutralizing antibodies are made. Neutralizing antibodies bind to a virus and effectively block infection, while non-neutralizing antibodies may bind to the virus but fail to control infection. As a result, during secondary infection, non-neutralizing antibodies are able to help the virus replicate and infect monocytes more efficiently, resulting in an increase in the severity of the dengue infection. 

The dengue virus is prevalent across the globe with more than 40% of the world’s population at risk for infection. The antibody-dependent enhancement of the dengue virus is of particular interest, as it is behind the severity of the illness during the second round of infection. To avoid being infected, the CDC advises wearing mosquito repellent, wearing long sleeves and pants in areas with large amounts of mosquitoes, and avoiding stagnant water.

Photo: Dengue fever symptoms.

1. Guzman MG, Harris E. DengueLancet. 2015;385(9966):453-465.

2. Bäck AT, Lundkvist A. Dengue viruses-an overviewInfect Ecol Epidemiol

3. Li L, Lok SM, Yu IM, et al. The flaviviruses virus precursor membrane-envelope protein complex: structure and maturation. Science. 

4. Yang S. How dengue infection hits harder the second time aroundScienceDaily.

5. Host response to the dengue virusNature. 

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