Dengue fever virus (DENV) is a single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same family include yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kyasanur forest disease virus, and Omsk hemorrhagic fever virus. Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses).
The dengue virus genome (genetic material) is about 11000 bases that codes for three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5), with short non-coding regions on both the 5' and 3' ends. There are four serotypes of the virus. All four serotypes can cause the full spectrum of disease. Infection with one serotype is believed to produce lifelong immunity it and short term protection from other serotypes.
The severe complications on secondary infection seem to occur particularly if someone previously exposed to DENV-1 then contracts DENV-2 or DENV-3, or if someone previously exposed to DENV-3 then acquires DENV-2.
When a mosquito carrying DENV bites a person, the virus enters the skin with the mosquito's saliva. It encounters and binds to a number of different cells in the skin, such as keratinocytes and Langerhans cells (a population of dendritic cells in the skin that identifies pathogens). Entry into cells is by binding of viral proteins to membrane proteins, such as the C-type lectins DC-SIGN, mannose receptor and CLEC5A. DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main one.The virus then enters the cells, and the dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is replicated in membrane-bound vesicles on the cell's endoplasmic reticulum, where the cell's protein synthesis apparatus produces new viral proteins, and the viral RNA is copied. Immature virus particles are transported from the endoplasmic reticulum to the Golgi apparatus, where the viral glycoproteins are modified. Mature new viruses bud on the surface of the infected cell and are released by exocytosis. They then enter other white blood cells (such as monocytes and macrophages).
The initial reaction of infected cells is to produce the cytokine interferon, which raises a number of defenses against viral infection through the innate immune system by augmenting the production of a large group of proteins (mediated by the JAK-STAT pathway). Some serotypes of DENV appear to have mechanisms to slow down this process. Interferon also activates the adaptive immune system, which leads to the generation of antibodies against the virus as well as T cells that directly attack any cell infected with the virus. Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis (ingestion by specialized cells) and destruction, but some bind the virus less well and appear instead to deliver the virus into a part of the phagocytes where it is not destroyed but is able to duplicate further.
It is not entirely clear why secondary infection with a different strain of DENV places people at risk of dengue hemorrhagic fever and dengue shock syndrome. The most widely accepted hypothesis is that of antibody-dependent enhancement (ADE). The exact mechanism behind ADE is unclear. It may be caused by poor binding of non-neutralizing antibodies and delivery into the wrong compartment of phagocytes. There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications, and a role for low-avidity T cells and soluble factors (such as cytokines and the complement system) is implied by various lines of research.
Severe disease is marked by two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered coagulation (blood clotting). Endothelial dysfunction leads to the leakage of fluid from the blood vessels into the chest and abdominal cavities, while coagulation disorder is responsible for the bleeding complications. Higher levels of virus in the blood and involvement of other organs (such as the bone marrow and the liver) are associated with more severe disease. Cells in the affected organs die, leading to the release of cytokines and activation of both coagulation and fibrinolysis (the opposing systems of blood clotting and clot degradation). These alterations together lead to both endothelial dysfunction and coagulation disorder.
The dengue virus genome (genetic material) is about 11000 bases that codes for three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5), with short non-coding regions on both the 5' and 3' ends. There are four serotypes of the virus. All four serotypes can cause the full spectrum of disease. Infection with one serotype is believed to produce lifelong immunity it and short term protection from other serotypes.
The severe complications on secondary infection seem to occur particularly if someone previously exposed to DENV-1 then contracts DENV-2 or DENV-3, or if someone previously exposed to DENV-3 then acquires DENV-2.
When a mosquito carrying DENV bites a person, the virus enters the skin with the mosquito's saliva. It encounters and binds to a number of different cells in the skin, such as keratinocytes and Langerhans cells (a population of dendritic cells in the skin that identifies pathogens). Entry into cells is by binding of viral proteins to membrane proteins, such as the C-type lectins DC-SIGN, mannose receptor and CLEC5A. DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main one.The virus then enters the cells, and the dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is replicated in membrane-bound vesicles on the cell's endoplasmic reticulum, where the cell's protein synthesis apparatus produces new viral proteins, and the viral RNA is copied. Immature virus particles are transported from the endoplasmic reticulum to the Golgi apparatus, where the viral glycoproteins are modified. Mature new viruses bud on the surface of the infected cell and are released by exocytosis. They then enter other white blood cells (such as monocytes and macrophages).
The initial reaction of infected cells is to produce the cytokine interferon, which raises a number of defenses against viral infection through the innate immune system by augmenting the production of a large group of proteins (mediated by the JAK-STAT pathway). Some serotypes of DENV appear to have mechanisms to slow down this process. Interferon also activates the adaptive immune system, which leads to the generation of antibodies against the virus as well as T cells that directly attack any cell infected with the virus. Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis (ingestion by specialized cells) and destruction, but some bind the virus less well and appear instead to deliver the virus into a part of the phagocytes where it is not destroyed but is able to duplicate further.
It is not entirely clear why secondary infection with a different strain of DENV places people at risk of dengue hemorrhagic fever and dengue shock syndrome. The most widely accepted hypothesis is that of antibody-dependent enhancement (ADE). The exact mechanism behind ADE is unclear. It may be caused by poor binding of non-neutralizing antibodies and delivery into the wrong compartment of phagocytes. There is a suspicion that ADE is not the only mechanism underlying severe dengue-related complications, and a role for low-avidity T cells and soluble factors (such as cytokines and the complement system) is implied by various lines of research.
Severe disease is marked by two problems: dysfunction of endothelium (the cells that line blood vessels) and disordered coagulation (blood clotting). Endothelial dysfunction leads to the leakage of fluid from the blood vessels into the chest and abdominal cavities, while coagulation disorder is responsible for the bleeding complications. Higher levels of virus in the blood and involvement of other organs (such as the bone marrow and the liver) are associated with more severe disease. Cells in the affected organs die, leading to the release of cytokines and activation of both coagulation and fibrinolysis (the opposing systems of blood clotting and clot degradation). These alterations together lead to both endothelial dysfunction and coagulation disorder.
