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Dengue virus infection usually causes dengue fever (DF) also referred to as breakbone fever. The infection caused by the virus is most of the time self limiting and may be characterized by the biphasic fever (cycle of sudden changes in body temperatures from normal to high), rash, myalgia (muscle pain), and leukopenia (lower than normal count white blood cells). Even though dengue fever is not fatal, there is risk of it developing into dengue hemorrhagic fever (DHF). Some of the characteristic presentations of DHF include increased permeability of blood vessels and abnormalities in hemostasis. Sever progression of DHF can lead to dengue shock syndrome (DSS). This is a hypovolemic shock that leads to concentration of blood due to loss of fluid and can result in death of the patient (1, 2).
The pathogenesis of dengue virus infection to DHF and DSS is not well understood. Several hypotheses have been proposed to explain the pathogenesis of the infection caused by dengue virus. One of the hypotheses of infection is antibody-dependent enhancement (ADE). According to this, a patient with a second time dengue infection from a different serotype of the virus possesses antibodies that cannot neutralize the new serotype: however these antibodies serve to augment the infection even further. Another proposed hypothesis for DHF is the immunopathogenesis hypothesis. According to this, the antibodies from previous infection bind to the virus particles and instead of neutralizing it help it gain entry into monocytes. Presentation of the dengue antigen causes an increase in the production of T-cells that are specific for dengue virus. Production of cytokines like Interferon - γ (IFN-γ), Interleukin - 2 (IL - 2), Tumor necrosis factor α (TNFα) is caused by the T-cells. These compounds assist in lysis of the monocytes that have been infected with dengue. The formation of the virus - antibody complex formation leads to the activation of the complement cascade and also leads to the release of cytokines C3a and C5a. These cytokines directly increase the permeability of blood vessels. All of the above factors combined together lead to increased endothelial leakage in a secondary dengue infection. An alternative hypothesis of dengue infection pathogenesis is the virus virulence hypotheses. It states the virulence of the strain of the dengue virus a patient is infected with determines if they progresses to DHF or DSS from dengue fever (1).
A review study conducted by the National Center for Genetic Engineering and Biotechnology and Biotechnology, Thailand provides an alternative hypothesis for pathogenesis of DHF/DSS by looking closely at events that occur during the acute disease stage. Some of these events include hyper-thermal factors, physical status of virus in an infected individual, conditioning of neutralizing antibody assay in dengue virus infection, concept of vector transmission, and innate immune system. An interesting finding from looking at hyperthermal factors was the increase in susceptibility of cells to viral infection under such conditions. This finding indicates that scientists should examine more closely cytokine release that directly or indirectly causes a thermal response to dengue virus. This examination may lead to the possible identification in the factors that distinguish DF from DHF or DSS. One concern that scientists have when dealing with dengue virus is the lack of information on the physical status of viremia caused by dengue. Studies have shown that infections in which the virus is associated with cells as compared to infections in which the virus is in the plasma are normally more severe. However, the mechanism of the virus getting into the cell is not well understood. A clear understanding of this factor may help in the design of preventative vaccines as well as the pathogenesis of DHF/DSS. The next factor studied by the group was the neutralizing antibody assay. Thus far this assay has only been conducted with cultures of dengue virus grown in vitro; this may not be representative of the wildtype dengue strains. Therefore, the assay needs to be conducted with virus isolated from patients to obtain a better understanding of its pathogenesis. After analysis of the above factors the researcher's have proposed that involvement of platelets and natural antibody IgM play an important role in infection with dengue prior to the appearance of symptoms (2).
Natural IgM antibody production is controlled by CD5 and B cells and these antibodies are actually part of the body's innate immune response. These non-specific antibodies assist with uptake of the virus and presentation of viral antigens to the B cells via complement. The interesting finding here is the fact that the primary cells infected by dengue virus are B cells. It is also believed that IgM is a strong classical complement pathway activator. Another important finding has been the identification of the immune complexes comprised of the virus particle and IgM antibodies in association with platelets from patients with DHF/DSS. These complexes have also been isolated from the cutaneous rashes of dengue patients. This hypothesis suggests that there may be a possibility that immune complexes that attach to the surface of platelets may play a major role in the destruction of platelets in the liver and the spleen. This is what causes thrombocytopenia, which is a characteristic manifestation of DHF. It is also proposed that the degree of the thrombocytopenia maybe related to the severity of DHF. Also, these platelets have been shown to provide protection from circulating antibodies and serve as a site of replication for the virus (2).
Some of the clinical manifestations of dengue have been explained briefly by the above hypotheses. However, due to limited available information on the matter not all the symptoms can be explained. The clinical manifestations of DF include an acute fever with headaches, a rash, muscle and joint pain, leucopenia, and thrombocytopenia. The symptoms normally last 2 -7 days. DHF causes vascular problems as well as blood clotting problems. Immunopathogenesis is generally is associated with the endothelial damage, thrombocytopenia, and hemorrhage (1). Even though a lot of progress has been made in understanding pathogenesis of dengue, there is a severe need for the development of a animal model system to improve our understandingof the immunological response to the virus as well as develop a vaccine for it.