Abstract
Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings
Highlights
During the first half of the 20th century, human responses to dengue virus (DENV) infection were described in multiple studies on hundreds of adult volunteers in different parts of the world[1,2,3,4,5,6,7,8,9]
On the basis of these case descriptions, many earlier 19th and 20th century outbreaks were identified as dengue fever (DF)
DENVs were identified as the cause of a fatal hemorrhagic fever in Southeast Asian children with few features of DF10,11
Summary
During the first half of the 20th century, human responses to dengue virus (DENV) infection were described in multiple studies on hundreds of adult volunteers in different parts of the world[1,2,3,4,5,6,7,8,9]. Antibodydependent enhancement of dengue infection (ADE) (#2), satisfies this requirement, whereas hypotheses #1 (acute immune complex disease), #3 (exaggerated T-cell response), #5 (heterophile immunity), and #6 (original antigenic sin) do not These hypotheses are unable to explain why DVPS accompanies a primary DENV infection in infants who circulate passively acquired dengue antibodies. DENV 2, 3, and 4 infections in type I and II interferon receptor-deficient mice produce a non-paralytic lethal disease accompanied by many features of DVPS, high levels of virus in tissues and circulating in blood and efferent phenomena, a cytokine storm, low platelet counts, elevated hematocrit, increased vascular permeability, and intestinal hemorrhage[75,76,77]. Grant information The author(s) declared that no grants were involved in supporting this work
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