Dengue virus

About: Dengue virus is a research topic. Over the lifetime, 12671 publications have been published within this topic receiving 461406 citations. The topic is also known as: DENV.

Slower rates of clearance of viral load and virus-containing immune complexes in patients with dengue hemorrhagic fever.

Abstract: Background. Although previous studies have revealed the contribution of an initial high level of dengue virus replication to the severe and potentially life-threatening diseases dengue hemorrhagic fever (DHF) and dengue shock syndrome, the involvement of dengue virus in the immuopathological processes during the transition from fever to defervescence, which is a critical stage in determining the progression to DHF, has not been appreciated. Previously, we reported that dengue virus can be detected in the immune complexes of patients with DHF during this period. Methods. We investigated plasma dengue viral load, virus in immune complexes, antibody response, complements, and cytokines for 54 patients with dengue fever (a relatively mild form of disease) and 49 patients with DHF. The patients had confirmed secondary infection with dengue virus type 2 from a large outbreak in southern Taiwan in 2002. Results. Patients with DHF had a significantly higher viral load and a slower rate of clearance than patients with dengue fever. For viral loads >5.7 log RNA copies/mL on the day of defervescence, the positive and negative predictive values for DHF are 0.88 and 0.95, respectively. A higher level and slower decline of dengue virus-containing immune complexes (and a subsequently higher elevation of C5a and soluble interleukin 2 receptor) were found in patients with DHF, compared with patients with dengue fever. Conclusions. These findings indicate that slower rates of clearance of viral load and virus-containing immune complexes are associated with subsequent immune activation and contribute to the progression of DHF at this critical stage. Moreover, viral load on the day of defervescence can predict cases of DHF.

Dengue in Vietnamese Infants—Results of Infection-Enhancement Assays Correlate with Age-Related Disease Epidemiology, and Cellular Immune Responses Correlate with Disease Severity

Abstract: Dengue is a well-documented public-health burden in many developing countries [1, 2]. Any of the 4 serotypes of dengue virus (DENV)—DENV1-DENV4—can cause a spectrum of outcomes in humans, ranging from asymptomatic infection to clinically significant disease. Severe disease is called “dengue hemorrhagic fever” (DHF) and is characterized by systemic capillary leakage, thrombocytopenia, and, in severe cases, hypovolemic shock. Substantial epidemiological evidence indicates that DHF in children and adults is typically associated with secondary infection caused by a DENV serotype distinct from that present when an individual is first exposed to DENV [3-6]. In contrast, DHF also occurs in primary DENV infections in infants born to dengue-immune mothers [7, 8]. A unifying hypothesis that explains the age-related epidemiology of DHF is a process called “antibody-dependent enhancement” (ADE) of disease [9]. The ADE model postulates that cross-reactive but subneutralizing levels of DENV-reactive IgG, acquired either passively or because of a previous infection, enhance DENV’s infectivity of Fc receptor-bearing cells. ADE could conceptually result in higher viral burdens in vivo and thereby precipitate some of the clinical events in dengue. Consistent with this model, children with secondary infections and DHF have higher initial plasma viral loads [10-12]. DHF in secondary infections is also associated with both significantly greater plasma concentrations of inflammatory cytokines [13-15] and increased frequencies of activated lymphocytes, compared with those in patients with milder disease [16, 17], presumably in response to higher viral burdens in DHF. Although much less is known about the pathogenesis of dengue in infants, previous studies by our group have suggested that, at least at the time of study enrollment, viral parameters are not associated with disease severity [8]. A critical challenge in dengue pathogenesis and vaccinology is to determine whether the biological character of ADE when measured in vitro can be correlated with disease outcomes and/or epidemiology. Previous prospective studies of children that have attempted to link the ADE phenomenon with disease outcomes in secondary infection but that have employed different methodologies have yielded conflicting results [18, 19]. Kliks et al. have described, in primary infections, a correlation between ADE activity in diluted maternal serum and the age at DHF onset in 13 Thai infants [20]. Against this backdrop, the aim of the present study was to correlate ADE with disease epidemiology in infants and to determine whether innate or acquired immune responses in infants with dengue, responses possibly triggered by ADE-mediated DENV infection, would correlate with disease severity. Our findings are consistent with the notion that infection-enhancing antibody plays a role in the pathogenesis of DHF in infants. Furthermore, we identified aspects of the infant innate and acquired immune response that are associated with disease severity.

Cholesterol Effectively Blocks Entry of Flavivirus

Abstract: Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-β-cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle.

The Pathology of Severe Dengue in Multiple Organs of Human Fatal Cases: Histopathology, Ultrastructure and Virus Replication

Abstract: Dengue is a public health problem, with several gaps in understanding its pathogenesis. Studies based on human fatal cases are extremely important and may clarify some of these gaps. In this work, we analyzed lesions in different organs of four dengue fatal cases, occurred in Brazil. Tissues were prepared for visualization in optical and electron microscopy, with damages quantification. As expected, we observed in all studied organ lesions characteristic of severe dengue, such as hemorrhage and edema, although other injuries were also detected. Cases presented necrotic areas in the liver and diffuse macro and microsteatosis, which were more accentuated in case 1, who also had obesity. The lung was the most affected organ, with hyaline membrane formation associated with mononuclear infiltrates in patients with pre-existing diseases such as diabetes and obesity (cases 1 and 2, respectively). These cases had also extensive acute tubular necrosis in the kidney. Infection induced destruction of cardiac fibers in most cases, with absence of nucleus and loss of striations, suggesting myocarditis. Spleens revealed significant destruction of the germinal centers and atrophy of lymphoid follicles, which may be associated to decrease of T cell number. Circulatory disturbs were reinforced by the presence of megakaryocytes in alveolar spaces, thrombus formation in glomerular capillaries and loss of endothelium in several tissues. Besides histopathological and ultrastructural observations, virus replication were investigated by detection of dengue antigens, especially the non-structural 3 protein (NS3), and confirmed by the presence of virus RNA negative strand (in situ hybridization), with second staining for identification of some cells. Results showed that dengue had broader tropism comparing to what was described before in literature, replicating in hepatocytes, type II pneumocytes and cardiac fibers, as well as in resident and circulating monocytes/macrophages and endothelial cells.