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One of the most dangerous viruses still around today is the Dengue virus. It was first identified in the late 1700s, and has survived to this day to continue to infect millions of people around the world. The Dengue virus is a member of the Flaviviridae family, and there are four serotypes of the virus. It is spread when an Aedes aegypti mosquito vector bites a human host, thus transmitting the Dengue virus that they are carrying. The female mosquitoes lay their eggs on the side of containers that hold water. The larvae hatch when they come in contact with water, usually from the rain. They go through several instars before they undergo metamorphosis into a pupa. The pupa then change until they become adult mosquitoes (CDC). The Dengue virus is found in several countries around the world, including India and Africa. It causes Dengue Hemorrhagic fever, which is also known as breakbone fever. It causes extremely high fevers and severe pain in muscles and joints. This disease can be fatal if it is not treated immediately. There are no government programs currently in place in most of the endemic countries, so the lack of effort to destroy these viral vectors is now causing a global re-emergence of Dengue virus infection.
The viral genome is made up of a positive sense RNA of approximately 11 kb. It has the caps at the 5' end but does not have a poly-A tail. There are various proteins that are encoded by the genome. There are structural proteins which include C, prM, and E. There are also nonstructural proteins which include NS1, NS2A/B, NS3, NS4A/B, and NS5, which are all involved in viral RNA replication (Perera and Kuhn). The Dengue viruses have an outer glycoprotein shell and a lipid bilayer which they acquire from their host. The outer shell is comprised of 2 main proteins, the E and M proteins. The E proteins are viral envelope proteins that help the virus bind to the host cell receptor (Acosta, Damonte and Talarico). These E proteins are composed of 3 domains, the most important of these being Domain II. The fusion peptide is found on the tip of domain II, and it is used to gain entry into the target cell. M proteins are transmembrane proteins that are found under the envelop proteins. These viruses also have nucleocapsids. These capsid proteins, or C proteins, are found within the lipid bilayer. These C proteins translocate the M proteins into the ER. The glycoprotein shell of the virus is made up of 180 copies of each of the E proteins and M proteins (Perera and Kuhn). As the virus matures, these proteins undergo conformational changes. The changes in the E proteins determine if the virion is in the mature or immature form. The immature virion has a spiky appearance due to the E and M proteins that extend out as trimeric spikes from the surface of the particle. The conformational changes of these proteins are a result of a decreased pH in the Golgi as it passes through. When the virus is in the Golgi, the host enzyme furin cleaves the pr peptide from the M protein, and that pr peptide acts as a cap on the E protein, enticing the E proteins to stay flat against the virion surface. The virion is now in its mature form. It is very smooth in appearance, as the E proteins, which are found as homodimers, lie flat against the surface of the virus. When the virion matures, the furin is cleaved, and the virus is released in the extracellular space, and the pr peptide is released (Perera and Kuhn).
NS1 proteins are non-structural proteins that are converted from monomer to dimer in the ER. Some of the NS1 associates with the intracellular organelles where it is involved in viral replication. The rest of the protein stays associated with the plasma membrane. The NS1 protein is very important in maintaining viral viability. When infected with Dengue virus, antibodies are produced against the NS1 protein. These antibodies react with the viral antigens to produce the symptoms of Dengue hemorrhagic fever ("Dengue Virus NS1 Glycoprotein Protein."). NS3 protein is a protease helicase that, along with its co-factor NS2B, cleaves the polyprotein to produce individual proteins. This particular protease processes most of the non-structural proteins ( Jacobs, Robinson, Bletchly et al.) NS2A and NS2B are both transmembrane proteins. It is believed that NS2A protein is involved in viral assembly. It may coordinate the shift between RNA packaging and RNA replication. NS2B is involved in proteolytic cleavage (Lindenbach, Thiel, and Rice 1109-1111). The most conserved protein of the Dengue virus is the NS5 protein. It has a RNA-dependent-RNA-polymerase on its C-terminal end which is involved in replicating the viral genome (Lindenbach, Thiel, and Rice 1111).
The lifecycle of the virus begins when the E protein of the virus attaches to the cell receptor, and the virus becomes endocytosed. It is unknown as to which host receptors they utilize. Some of the receptors that have been proposed are the DC-SIGN and the heparan sulfate receptors. Several studies have shown that heparan sulfate proteoglycan is a receptor on the cell surface and in the extracellular matrix that is involved in the attachment of the Dengue virus to the cell (Summerford and Samulski). The DC-SIGN is a Dendritic Cell Specific Intercellular adhesion molecule-3-Grabbing Non-integrin. It is a receptor on macrophages and dendritic cells that recognize viral pathogen associated molecular patterns. When the PAMP is recognized, phagocytosis occurs. When the pH of the endosome decreases, the viral membrane fuses with the cell membrane. The nucleocapsid uncoats and the RNA genome is released into the cytoplasm. There, the genome has several functions. It functions as mRNA, which carries out all the translational processes of the viral proteins. It also contains a viral RNA-dependent-RNA-polymerase which allows it to replicate the viral genome and produce a template. It is also involved in packaging the genome into new viral particles. The viral proteins are produced in a long polyprotein configuration, and this polyprotein is cleaved by host signalases that are found in the lumen of the ER. RNA replication occurs via synthesis of a minus strand RNA complement. These minus strand complements are later used to make more plus strand RNA. Progeny virions are produced by budding into the ER, going through the host secretory pathway, and releasing into the cell surface (Lindenbach, Thiel, and Rice 1103-1105).
When infection occurs, both the innate and adaptive immune responses are activated. The virus has several targets, including dendritic cells, fibroblasts, and monocytes. When fibroblasts and monocytes are infected, they produce interferons (Rothman). Interferons, or IFNs, are proteins that are released in response to the presence of viruses. They allow cells to communicate with each other so that they know if an immune response should be mounted against a detected pathogen. Cells that are infected with the virus may be lysed by CD4+ and CD8+ T cells which produce cytokines like interferons and tumor necrosis factor Î± (Rothman). The non-structural proteins of the virus inhibit the interferons so that they cannot activate the immune system (Lindenbach, Thiel, and Rice 1112).
During activation of humoral immune response, different types of antibodies are produced at different times. In primary infection, neutralizing antibodies are produced, and they inhibit viral replication and activate the T cells that lyse the infected cells (Luplertlop). The antibodies that are produced provide immunity against that particular serotype if it is ever encountered again. During a secondary infection, people that have already been infected with one serotype of the virus and subsequently infected with another serotype. During this phase, enhancing antibodies are produced. They help the virus enter the cell and promote replication. The T cells can no longer inhibit the viral infection. It is most likely the cause of more severe forms of disease such as Dengue hemorrhagic fever (Luplertlop).
It is very difficult to produce a vaccine against the Dengue virus.Â There are 4 serotypes of this virus, so if a vaccine is produced, it must be able to provide immunity against each of these serotypes. Another reason that scientists have found it to be so problematic is that they do not have adequate animal models that can be used (WHO). Â
The incubation period of the virus is anywhere from 3-15 days before the symptoms start to appear. Viral infection may cause a mild form of disease known as Dengue fever, which is hardly ever fatal. It may begin with chills, headaches, and joint and muscle pain. Then, a fever begins to develop, getting as high as 104 degrees. The eyes become red, and the lymph nodes become swollen. A rash will come and go during the first few days as the symptoms develop, until it returns and spreads to cover the entire body, except for the face (CDC and MedicineNet). There are no long term consequences associated with Dengue virus infection.
The more severe form is infection is known as Dengue hemorrhagic fever, which is characterized as having a fever that lasts more than a couple of days. As the fever begins to drop, other things may start to happen. This is the beginning of the period in which the capillaries begin to leak fluid into the chest and lung cavities, causing the circulatory system to fail and the patient to go into shock. This is a result of the dendritic cells overproducing metalloproteinase 9, which promotes endothelial permeability (Luplerdlop, Misse, Bray, et. al). Once this occurs, the patient is likely to die unless they are immediately transported to the hospital (CDC).
There are no vaccines available to treat someone infected with the Dengue virus. The main focus on infected individuals is to treat the symptoms. Pain killers such as Tylenol and codeine may be administered to help treat the joint and muscle pain, and also to help reduce the fever. With proper rest, the patient should recover in approximately 1 month.
If a person develops Dengue Hemorrhagic Fever, they should be hospitalized immediately. The prognosis of someone who is not hospitalized is around 50%, whereas is they are hospitalized, the prognosis increases dramatically with a mortality rate of just 3%. These patients must be kept hydrated in order to prevent shock (MedIndia).
Several steps may be taken in order to prevent infection. The most important thing to remember is to avoid the mosquito vectors that carry the virus. Mosquito netting is one way to avoid being bitten. While performing everyday tasks, it would be a good idea to cover up with the mosquito net in order to deter the viral vectors. Also, using mosquito repellant is a good idea. The Aedes aegypti mosquito is most active during the day, so it is best to avoid going outside, and also avoiding standing water. Covering up with proper clothing is also important. Expose as little skin as possible by wearing long sleeved shirts, long pants, and proper protective footwear (CDC).
As of today, approximately 2.5 billion people live in areas where the transmission of Dengue virus is a possibility. It is endemic in several countries in Asia, the Pacific, the Americas, Africa, and the Caribbean. According to the World Health Organization, around 50-100 million infections occur every year. Of these, most of the victims are likely to be children. The Aedes aegypti mosquitoes are not found in the Unites States, so the most likely cause of infection is due to people traveling in infected areas around the world (CDC).
A study was done to determine the impact of Dengue Hemorrhagic fever in a small area of Thailand. Researchers found that the cost of hospitalization as well as the loss of income with regards to the number of people infected per family, the financial loss was approximately $61, which is more than the average monthly income in Thailand. Even if the infected people survive, the stress of such a financial burden makes it more and more difficult for people to survive (Clark, Mammen, Nisalak, et al.).
Dengue virus infection is still very much an issue today. Since there have not been any cures developed against the virus, it is extremely important to develop more efficient ways to prevent infection. If government programs were set up, and more effort was put into researching a possible cure, it would help tremendously in the countries that are being affected. By destroying the mosquito vectors, the virus would be unable to infect their human hosts, and the virus would not be able to spread. While Dengue hemorrhagic fever is a very severe disease, it is highly treatable in a hospital. However, poverty runs high in most of the infected countries, so people are less likely to seek professional health, thus putting there lives in danger. Before 1970, only 9 countries where shown the have experienced Dengue hemorrhagic fever, but by 1995, four times as many countries had been infected (WHO). With the spread of this virus running so rampant, we will hopefully on day be able to identify a means of removing the threat of Dengue infection altogether.