Dengue fever

About: Dengue fever is a research topic. Over the lifetime, 17463 publications have been published within this topic receiving 485745 citations. The topic is also known as: Dengue & dengue disease.

Understanding dengue pathogenesis: implications for vaccine design

Abstract: In the second half of the twentieth century dengue spread throughout the tropics, threatening the health of a third of the world's population. Dengue viruses cause 50-100 million cases of acute febrile disease every year, including more than 500,000 reported cases of the severe forms of the disease--dengue haemorrhagic fever and dengue shock syndrome. Attempts to create conventional vaccines have been hampered by the lack of suitable experimental models, the need to provide protection against all four serotypes simultaneously and the possible involvement of virus-specific immune responses in severe disease. The current understanding of dengue pathogenesis is outlined in this review, with special emphasis on the role of the immune response. The suspected involvement of the immune system in increased disease severity and vascular damage has raised concerns about every vaccine design strategy proposed so far. Clearly more research is needed on understanding the correlates of protection and mechanisms of pathogenesis. There is, however, an urgent need to provide a solution to the escalating global public health problems caused by dengue infections. Better disease management, vector control and improved public health measures will help reduce the current disease burden, but a safe and effective vaccine is probably the only long-term solution. Although concerns have been raised about the possible safety and efficacy of both conventional and novel vaccine technologies, the situation is now so acute that it is not possible to wait for the perfect vaccine. Consequently the careful and thorough evaluation of several of the current candidate vaccines may be the best approach to halting the spread of disease.

RNA structures that resist degradation by Xrn1 produce a pathogenic Dengue virus RNA

Abstract: More than 40% of people around the globe are at risk of being bitten by mosquitoes infected with the virus that causes Dengue fever. Every year, more than 100 million of these individuals are infected. Many develop severe headaches, pain, and fever, but some develop a life-threatening condition where tiny blood vessels in the body begin to leak. If not treated quickly, this more severe manifestation of the illness can lead to death. There are currently no specific therapies or vaccines against Dengue or many other closely related viruses such as West Nile and Japanese Encephalitis. These viruses use instructions encoded in a single strand of RNA to take over an infected cell and to reproduce. The viruses also exploit an enzyme that cells use to destroy RNA to instead produce short stretches of RNA called sfRNAs that, among other things, may help the virus to avoid the immune system of its host. Understanding exactly how Dengue and other viruses thwart this enzyme—which is called Xrn1—may help scientists develop treatments or vaccines for these diseases. Chapman et al. have now shown that Dengue virus RNA contains a number of RNA elements that prevent it being completely degraded by the Xrn1 enzyme. In particular, a junction formed by three RNA helixes is critical for stopping the enzyme in its tracks, leaving the disease-associated sfRNA behind. A single mutation in the Dengue RNA disrupts the structure of the three-helix junction and allows the enzyme to completely destroy the RNA. A similar mutation was also made in the West Nile virus RNA and when human cells were infected with the mutated West Nile virus, the short sfRNAs were not produced. Treatments or vaccines targeting this structure may therefore help reduce illness associated with Dengue and related viruses.

Alterations in the Aedes aegypti transcriptome during infection with West Nile, dengue and yellow fever viruses.

Abstract: West Nile (WNV), dengue (DENV) and yellow fever (YFV) viruses are (re)emerging, mosquito-borne flaviviruses that cause human disease and mortality worldwide. Alterations in mosquito gene expression common and unique to individual flaviviral infections are poorly understood. Here, we present a microarray analysis of the Aedes aegypti transcriptome over time during infection with DENV, WNV or YFV. We identified 203 mosquito genes that were ≥5-fold differentially up-regulated (DUR) and 202 genes that were ≥10-fold differentially down-regulated (DDR) during infection with one of the three flaviviruses. Comparative analysis revealed that the expression profile of 20 DUR genes and 15 DDR genes was quite similar between the three flaviviruses on D1 of infection, indicating a potentially conserved transcriptomic signature of flaviviral infection. Bioinformatics analysis revealed changes in expression of genes from diverse cellular processes, including ion binding, transport, metabolic processes and peptidase activity. We also demonstrate that virally-regulated gene expression is tissue-specific. The overexpression of several virally down-regulated genes decreased WNV infection in mosquito cells and Aedes aegypti mosquitoes. Among these, a pupal cuticle protein was shown to bind WNV envelope protein, leading to inhibition of infection in vitro and the prevention of lethal WNV encephalitis in mice. This work provides an extensive list of targets for controlling flaviviral infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses.

Attenuation Markers of a Candidate Dengue Type 2 Vaccine Virus, Strain 16681 (PDK-53), Are Defined by Mutations in the 5′ Noncoding Region and Nonstructural Proteins 1 and 3

Abstract: The genome of a candidate dengue type 2 (DEN-2) vaccine virus, strain PDK-53, differs from its DEN-2 16681 parent by nine nucleotides. Using infectious cDNA clones, we constructed 18 recombinant 16681/PDK-53 viruses to analyze four 16681-to-PDK-53 mutations, including 5' noncoding region (5'NC)-57 C-to-T, premembrane (prM)-29 Asp-to-Val (the only mutation that occurs in the structural proteins), nonstructural protein 1 (NS1)-53 Gly-to-Asp, and NS3-250 Glu-to-Val. The viruses were studied for plaque size, growth rate, and temperature sensitivity in LLC-MK(2) cells, growth rate in C6/36 cells, and neurovirulence in newborn mice. All of the viruses replicated to peak titers of 10(7.3) PFU/ml or greater in LLC-MK(2) cells. The crippled replication of PDK-53 virus in C6/36 cells and its attenuation for mice were determined primarily by the 5'NC-57-T and NS1-53-Asp mutations. The temperature sensitivity of PDK-53 virus was attributed to the NS1-53-Asp and NS3-250-Val mutations. The 5'NC-57, NS1-53, and NS3-250 loci all contributed to the small-plaque phenotype of PDK-53 virus. Reversions at two or three of these loci in PDK-53 virus were required to reconstitute the phenotypic characteristics of the parental 16681 virus. The prM-29 locus had little or no effect on viral phenotype. Sequence analyses showed that PDK-53 virus is genetically identical to PDK-45 virus. Restriction of the three major genetic determinants of attenuation markers to nonstructural genomic regions makes the PDK-53 virus genotype attractive for the development of chimeric DEN virus vaccine candidates.