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.

Dengue Virus Structural Differences That Correlate with Pathogenesis

Abstract: The understanding of dengue virus pathogenesis has been hampered by the lack of in vitro and in vivo models of disease. The study of viral factors involved in the production of severe dengue, dengue hemorrhagic fever (DHF), versus the more common dengue fever (DF), have been limited to indirect clinical and epidemiologic associations. In an effort to identify viral determinants of DHF, we have developed a method for comparing dengue type 2 genomes (reverse transcriptase PCR in six fragments) directly from patient plasma. Samples for comparison were selected from two previously described dengue type 2 genotypes which had been shown to be the cause of DF or DHF. When full genome sequences of 11 dengue viruses were analyzed, several structural differences were seen consistently between those associated with DF only and those with the potential to cause DHF: a total of six encoded amino acid charge differences were seen in the prM, E, NS4b, and NS5 genes, while sequence differences observed within the 5′ nontranslated region (NTR) and 3′ NTR were predicted to change RNA secondary structures. We hypothesize that the primary determinants of DHF reside in (i) amino acid 390 of the E protein, which purportedly alters virion binding to host cells; (ii) in the downstream loop (nucleotides 68 to 80) of the 5′ NTR, which may be involved in translation initiation; and (iii) in the upstream 300 nucleotides of the 3′ NTR, which may regulate viral replication via the formation of replicative intermediates. The significance of four amino acid differences in the nonstructural proteins NS4b and NS5, a presumed transport protein and the viral RNA polymerase, respectively, remains unknown. This new approach to the study of dengue virus genome differences should better reflect the true composition of viral RNA populations in the natural host and permit their association with pathogenesis.

Inhibition of interferon signaling by dengue virus

Abstract: Dengue virus is a worldwide-distributed mosquito-borne flavivirus with a positive strand RNA genome. Its transcribed polyprotein is cleaved by host- and virus-encoded peptidases into 10 proteins, some of which are of unknown function. Although dengue virus-infected cells seem to be resistant to the antiviral action of IFN, the viral products that mediate this resistance are unknown. Therefore, we have analyzed the ability of the 10 dengue virus-encoded proteins to antagonize the IFN response. We found that expression in human A549 cells of the dengue virus nonstructural proteins NS2A, NS4A, or NS4B enhances replication of an IFN-sensitive virus. Moreover, expression of NS4B and, to a lesser extent, of NS2A and NS4A proteins results in down-regulation of IFN-β-stimulated gene expression. Cells expressing NS4B or infected with dengue virus do not exhibit nuclear signal transducer and activator of transcription (STAT) 1 on treatment with IFN-β or IFN-γ, indicating that NS4B might be involved in blocking IFN signaling during dengue virus infections. This protein, encoded by a positive strand RNA virus, is implicated as an IFN-signaling inhibitor.

Prospects for a dengue virus vaccine.

Abstract: The number of cases of severe dengue disease continues to grow in endemic areas of southeast Asia, Central and South America, and other subtropical regions. Children bear the greatest burden of disease, and the development of an effective vaccine remains a global public health priority. A tetravalent vaccine is urgently needed and must be effective against all four dengue virus serotypes, be cost-effective and provide long-term protection. In this Review we discuss the unique immunological concerns in dengue virus vaccine development and the current prospects for the development of an acceptable vaccine, a goal that is likely to be reached in the near future.

Zika virus (II). Pathogenicity and physical properties

Abstract: 1. (1) A description is given of the adaptation to mice of two strains of Zika virus. Zika is the name of a forest area near Entebbe, Uganda, where both strains of virus were isolated. One of the strains was isolated from a pyrexial rhesus monkey which was being employed as a yellow fever sentinel and the other was obtained from a batch of A. africanus. 2. (2) The signs of infection in mice are described. While mice of all ages tested are susceptible to intracerebral inoculations with Zika mouse brain virus, mice of 2 weeks of age and over can rarely be infected by the intraperitoneal route. Mice younger than 2 weeks are highly susceptible to intraperitoneal inoculation of the virus. 3. (3) Zika virus is highly neurotropic in mice and no virus has been recovered from tissues other than the brains of infected mice. 4. (4) Cotton-rats, guineapigs and rabbits show no clinical signs of infection after intracerebral inoculation of late passage mouse brain virus. 5. (5) Monkeys develop an inapparent infection after subcutaneous inoculation with mouse brain virus. After intracerebral inoculation one of five monkeys showed a mild pyrexia, the others showed no signs of infection. Viraemia during the first week after inoculation has been found in all monkeys tested and antibody has been demonstrated by the 14th day after inoculation. 6. (6) Of 99 human sera tested, 6 (6.1 per cent.)-have neutralized more than 100 LD50 of virus. Antibody has also been found in the serum of one of 15 wild monkeys tested. 7. (7) The size of Zika virus is estimated to eb in the region of 30 to 45 mμ in diameter. The virus may be preserved up to 6 months in 50 per cent. glycerol and up to 30 months after drying. It is susceptible to anaesthetic ether and the thermal death point is 58°C. for 30 minutes. 8. (8) Neuronal degeneration, cellular infiltration and areas of softening are present in infected mouse brains. Cowdry type A inclusion bodies have been found, particularly in the brains of young mice showing extensive lesions.

Enzyme-Linked Immunosorbent Assay Specific to Dengue Virus Type 1 Nonstructural Protein NS1 Reveals Circulation of the Antigen in the Blood during the Acute Phase of Disease in Patients Experiencing Primary or Secondary Infections

Abstract: During flavivirus infection in vitro, nonstructural protein NS1 is released in a host-restricted fashion from infected mammalian cells but not vector-derived insect cells. In order to analyze the biological relevance of NS1 secretion in vivo, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) to detect the protein in the sera of dengue virus-infected patients. The assay was based on serotype 1 NS1-specific mouse and rabbit polyclonal antibody preparations for antigen immunocapture and detection, respectively. With purified dengue virus type 1 NS1 as a protein standard, the sensitivity of our capture ELISA was less than 1 ng/ml. When a panel of patient sera was analyzed, the NS1 antigen was found circulating from the first day after the onset of fever up to day 9, once the clinical phase of the disease is over. The NS1 protein could be detected even when viral RNA was negative in reverse transcriptase-PCR or in the presence of immunoglobulin M antibodies. NS1 circulation levels varied among individuals during the course of the disease, ranging from several nanograms per milliliter to several micrograms per milliliter, and peaked in one case at 50 μg/ml of serum. Interestingly, NS1 concentrations did not differ significantly in serum specimens obtained from patients experiencing primary or secondary dengue virus infections. These findings indicate that NS1 protein detection may allow early diagnosis of infection. Furthermore, NS1 circulation in the bloodstream of patients during the clinical phase of the disease suggests a contribution of the nonstructural protein to dengue virus pathogenesis.