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.

Reduced risk of disease during postsecondary dengue virus infections.

Abstract: Dengue virus (DENV) is the most prevalent arthropod-transmitted virus among humans, with conservative estimates placing half of the world's population at risk for infection [1, 2]. Dengue can be caused by any of 4 viral serotypes (DENV-1–4), and infection can lead to a range of outcomes, from subclinical infection to death [3]. Infection outcomes are determined by a suite of factors, including host susceptibility, virus genetics, cell-mediated immune response, and cross-reactive antibodies [4, 5]. Cross-reaction between preexisting DENV antibodies and virus of a heterotypic infecting serotype is due to the conservation of some viral envelope proteins across serotypes, which results in antibody binding to the virus particles without fully neutralizing them [6]. There is epidemiologic and in vitro evidence that these cross-reactive antibodies can enhance infection and disease severity during secondary infections (referred to as antibody-dependent enhancement [7–9]). It has also been inferred from hospital admissions data that severe disease is rare during third and fourth infections [10], suggesting that there is a protective effect conferred by cumulative cross-reactive antibodies. Despite the uncertainties, a general lesson from multiple-strain DENV mathematical models is that the effects of preexisting antibodies, either enhancing or protective, can significantly influence projected virus transmission and disease dynamics [11–15]. Because of the possibility for disease potentiation from subneutralizing antibodies, vaccine design efforts have aimed for a tetravalent formulation that simultaneously protects against all 4 DENV serotypes [16, 17]. Recent results from phase 2b trials of the leading vaccine candidate showed partial efficacy against DENV-1, DENV-3, and DENV-4 but did not protect against febrile illness associated with DENV-2 infection [18]. An important unanswered question concerns the effect that neutralizing antibody to ≥2 serotypes will have on disease burden and virus transmission. There is, therefore, a need for empirical data characterizing population-level outcomes of serial DENV infections. In this study, we used data from a longitudinal cohort in Iquitos, Peru, where prospective seroepidemiology and febrile surveillance studies have been ongoing since 1999. For the same individuals, biannual serological results were used to determine the baseline serostatus of participants, and door-to-door febrile surveillance paired with laboratory confirmation was used to identify subsequent disease due to a DENV infection. Of special interest were disease outcomes during third and fourth infections, which were classified together as postsecondary infections. Our data indicate that the risk of developing febrile dengue illness was significantly reduced in individuals with a history of ≥2 prior DENV exposures, despite the absence of preexisting antibodies specific to the infecting serotype.

Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype

Abstract: We demonstrated that the infection of humanized NOD-scid IL2rγ null mice with different strains (representing the four genotypes) of dengue virus serotype 2 (DEN-2) can induce the development of human-like disease, including fever, viremia, erythema, and thrombocytopenia. Newborn mice were irradiated and received transplants by intrahepatic inoculation of human cord blood-derived hematopoietic progenitor cells (CD34+). After 6 weeks, mouse peripheral blood was tested by flow cytometry to determine levels of human lymphocytes (CD45+ cells); rates of reconstitution ranged from 16 to 80% (median, 52%). Infection (with approximately 106 PFU, the equivalent of a mosquito bite) of these humanized mice with eight low-passage-number strains produced a high viremia extending to days 12 to 18 postinfection. We observed a significant decrease in platelets at day 10 in most of the mice and an increase in body temperature (fever) and erythema (rash) in comparison with humanized mice inoculated with cell culture medium only. Comparison of Southeast (SE) Asian and other genotype viruses (American, Indian, and West African) in this model showed significant differences in magnitude and duration of viremia and rash, with the SE Asian viruses always being highest. Indian genotype viruses produced lower viremias and less thrombocytopenia than the others, and West African (sylvatic) viruses produced the shortest periods of viremia and the lowest rash measurements. These results correlate with virulence and transmission differences described previously for primary human target cells and whole mosquitoes and may correlate with epidemiologic observations around the world. These characteristics make this mouse model ideal for the study of dengue pathogenesis and the evaluation of vaccine attenuation and antivirals.

Potential Antigenic Cross-reactivity Between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Dengue Viruses.

Abstract: BACKGROUND: Coronavirus disease 2019 (COVID-19) and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross-reactivity. METHODS: We analyzed clinical data and serum samples from 55 individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To assess dengue serology status, we used dengue-specific antibodies by means of lateral-flow rapid test, as well as enzyme-linked immunosorbent assay (ELISA). Additionally, we tested SARS-CoV-2 serology status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS: Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P = 2.5E-5). This includes 9 cases of positive immunoglobulin M (IgM), 2 cases of positive immunoglobulin G (IgG), and 1 case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in 2 additional subjects using envelope protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (P = 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. CONCLUSIONS: Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.

Tissue plasminogen activator induced by dengue virus infection of human endothelial cells.

Abstract: Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are severe complications of dengue virus (DV) infection. However, the pathogenesis of hemorrhage induced by dengue virus infection is poorly understood. Since endothelial cells play a pivotal role in the regulation of hemostasis, we studied the effect of DV infection on the production of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) in vitro using both primary isolated endothelial cells, human umbilical cord veins cells, and a human microvascular endothelial cell line. DV infection significantly induced the secretion of tPA but not PAI-1 of human endothelial cells. In addition, tPA mRNA of endothelial cells was induced by DV as demonstrated by RT-PCR. Antibody against IL-6 but not control antibody inhibited DV-induced tPA production of endothelial cells. Furthermore, a good correlation between sera levels of IL-6 and tPA was found in DHF but not DF patients. These results suggest that IL-6 can regulate DV-induced tPA production of endothelial cells, which may play important roles in the pathogenic development of DHF/DSS.

c-Src protein kinase inhibitors block assembly and maturation of dengue virus

Abstract: Dengue virus is a mosquito-borne flavivirus that represents an important emerging infectious disease and is an international health concern. Currently, there is no vaccine or effective antiviral therapy to prevent or to treat dengue virus infection. The slow progress in developing antiviral agents might be alleviated by the availability of efficient high-throughput anti-dengue virus screening assays. In this study, we report an immunofluorescence image-based assay suitable for identification of small molecule inhibitors of dengue virus infection and replication. Using this assay, we have discovered that inhibitors of the c-Src protein kinase exhibit a potent inhibitory effect on dengue virus (serotypes 1–4) and murine flavivirus Modoc. Mechanism of action studies demonstrated that the c-Src protein kinase inhibitor dasatinib prevents the assembly of dengue virions within the virus-induced membranous replication complex. These results demonstrate that this cell-based screen may provide a powerful means to identify new potential targets for anti-dengue drug development while simultaneously providing pharmacological probes to investigate dengue virus–host cell interactions at the biochemical level. Given the simplicity and excellent reproducibility of the assay, it should be useful in high-throughput screens of both small molecule and RNAi libraries when implemented on a robotic image-based high-throughput screen (HTS) platform. Given the reasonable clinical safety of inhibitors such as dasatinib and AZD0530, inhibitors of c-Src protein kinase may have the potential to become a new class of anti-dengue viral therapeutic agents.