Dengue fever, also known as breakbone fever, is a mosquito-borne tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles. In a small proportion of cases, the disease develops into the life-threatening dengue hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where dangerously low blood pressure occurs.
Dengue is transmitted by several species of mosquito within the genus Aedes, principally A. aegypti. The virus has five different types; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. As there is no commercially available vaccine, prevention is sought by reducing the habitat and the number of mosquitoes and limiting exposure to bites.
Treatment of acute dengue is supportive, using either oral or intravenous rehydration for mild or moderate disease, and intravenous fluids and blood transfusion for more severe cases. The number of cases of dengue fever has increased dramatically since the 1960s, with between 50 and 528 million people infected yearly. Early descriptions of the condition date from 1779, and its viral cause and transmission were understood by the early 20th century. Dengue has become a global problem since the Second World War and is endemic in more than 110 countries. Apart from eliminating the mosquitoes, work is ongoing on a dengue vaccine, as well as medication targeted directly at the virus.
Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. These mosquitoes usually live between the latitudes of 35° North and 35° South below an elevation of 1,000 metres (3,300 ft). They typically bite during the day, particularly in the early morning and in the evening, but they are able to bite and thus spread infection at any time of day all during the year. Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus, but it also circulates in nonhuman primates. An infection can be acquired via a single bite. A female mosquito that takes a blood meal from a person infected with dengue fever, during the initial 2–10 day febrile period, becomes itself infected with the virus in the cells lining its gut. About 8–10 days later, the virus spreads to other tissues including the mosquito’s salivary glands and is subsequently released into its saliva. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Aedes aegypti is particularly involved, as it prefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed on people rather than other vertebrates.
Dengue can also be transmitted via infected blood products and through organ donation. In countries such as Singapore, where dengue is endemic, the risk is estimated to be between 1.6 and 6 per 10,000 transfusions. Vertical transmission (from mother to child) during pregnancy or at birth has been reported. Other person-to-person modes of transmission have also been reported, but are very unusual. The genetic variation in dengue viruses is region specific, suggestive that establishment into new territories is relatively infrequent, despite dengue emerging in new regions in recent decades.
Mechanism
When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito’s saliva. It binds to and enters white blood cells, and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing a number of signaling proteins, such as cytokines and interferons, which are responsible for many of the symptoms, such as the fever, the flu-like symptoms and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to capillary permeability. As a result, less blood circulates in the blood vessels, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. Furthermore, dysfunction of the bone marrow due to infection of the stromal cells leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever.
Viral replication
Once inside the skin, dengue virus binds to Langerhans cells (a population of dendritic cells in the skin that identifies pathogens). The virus enters the cells through binding between viral proteins and membrane proteins on the Langerhans cell, specifically the C-type lectins called DC-SIGN, mannose receptor and CLEC5A.DC-SIGN, a non-specific receptor for foreign material on dendritic cells, seems to be the main point of entry. The dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is translated in membrane-bound vesicles on the cell’s endoplasmic reticulum, where the cell’s protein synthesis apparatus produces new viral proteins that replicate the viral RNA and begin to form viral particles. Immature virus particles are transported to the Golgi apparatus, the part of the cell where some of the proteins receive necessary sugar chains (glycoproteins). The now mature new viruses bud on the surface of the infected cell and are released by exocytosis. They are then able to enter other white blood cells, such as monocytes and macrophages.
The initial reaction of infected cells is to produce interferon, a cytokine that 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 dengue virus 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 replicate further.
