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.

Protective and enhancing HLA alleles, HLA-DRB1*0901 and HLA-A*24, for severe forms of dengue virus infection, dengue hemorrhagic fever and dengue shock syndrome.

Abstract: Background Dengue virus (DV) infection is one of the most important mosquito-borne diseases in the tropics. Recently, the severe forms, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), have become the leading cause of death among children in Southern Vietnam. Protective and/or pathogenic T cell immunity is supposed to be important in the pathogenesis of DHF and DSS. Methodology/Principal Findings To identify HLA alleles controlling T cell immunity against dengue virus (DV), we performed a hospital-based case control study at Children's Hospital No.2, Ho Chi Minh City (HCMC), and Vinh Long Province Hospital (VL) in Southern Vietnam from 2002 to 2005. A total of 211 and 418 patients with DHF and DSS, respectively, diagnosed according to the World Health Organization (WHO) criteria, were analyzed for their characteristic HLA-A, -B and -DRB1 alleles. Four hundred fifty healthy children (250 from HCMC and 200 from VL) of the same Kinh ethnicity were also analyzed as population background. In HLA class I, frequency of the HLA-A*24 showed increased tendency in both DHF and DSS patients, which reproduced a previous study. The frequency of A*24 with histidine at codon 70 (A*2402/03/10), based on main anchor binding site specificity analysis in DSS and DHF patients, was significantly higher than that in the population background groups (HCMC 02-03 DSS: OR = 1.89, P = 0.008, DHF: OR = 1.75, P = 0.033; VL 02-03 DSS: OR = 1.70, P = 0.03, DHF: OR = 1.46, P = 0.38; VL 04-05 DSS: OR = 2.09, P = 0.0075, DHF: OR = 2.02, P = 0.038). In HLA class II, the HLA-DRB1*0901 frequency was significantly decreased in secondary infection of DSS in VL 04-05 (OR = 0.35, P = 0.0025, Pc = 0.03). Moreover, the frequency of HLA-DRB1*0901 in particular was significantly decreased in DSS when compared with DHF in DEN-2 infection (P = 0.02). Conclusion This study improves our understanding of the risk of HLA-class I for severe outcome of DV infection in the light of peptide anchor binding site and provides novel evidence that HLA-class II may control disease severity (DHF to DSS) in DV infection.

Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease.

Abstract: The limited host tropism of numerous viruses causing disease in humans remains incompletely understood. One example is Zika virus (ZIKV), an RNA virus that has reemerged in recent years. Here, we demonstrate that ZIKV efficiently infects fibroblasts from humans, great apes, New and Old World monkeys, but not rodents. ZIKV infection in human—but not murine—cells impairs responses to agonists of the cGMP-AMP synthase/stimulator of IFN genes (cGAS/STING) signaling pathway, suggesting that viral mechanisms to evade antiviral defenses are less effective in rodent cells. Indeed, human, but not mouse, STING is subject to cleavage by proteases encoded by ZIKV, dengue virus, West Nile virus, and Japanese encephalitis virus, but not that of yellow fever virus. The protease cleavage site, located between positions 78/79 of human STING, is only partially conserved in nonhuman primates and rodents, rendering these orthologs resistant to degradation. Genetic disruption of STING increases the susceptibility of mouse—but not human—cells to ZIKV. Accordingly, expression of only mouse, not human, STING in murine STING knockout cells rescues the ZIKV suppression phenotype. STING-deficient mice, however, did not exhibit increased susceptibility, suggesting that other redundant antiviral pathways control ZIKV infection in vivo. Collectively, our data demonstrate that numerous RNA viruses evade cGAS/STING-dependent signaling and affirm the importance of this pathway in shaping the host range of ZIKV. Furthermore, our results explain—at least in part—the decreased permissivity of rodent cells to ZIKV, which could aid in the development of mice model with inheritable susceptibility to ZIKV and other flaviviruses.

Natural strain variation and antibody neutralization of dengue serotype 3 viruses.

Abstract: Dengue viruses (DENVs) are emerging, mosquito-borne flaviviruses which cause dengue fever and dengue hemorrhagic fever. The DENV complex consists of 4 serotypes designated DENV1-DENV4. Following natural infection with DENV, individuals develop serotype specific, neutralizing antibody responses. Monoclonal antibodies (MAbs) have been used to map neutralizing epitopes on dengue and other flaviviruses. Most serotype-specific, neutralizing MAbs bind to the lateral ridge of domain III of E protein (EDIII). It has been widely assumed that the EDIII lateral ridge epitope is conserved within each DENV serotype and a good target for vaccines. Using phylogenetic methods, we compared the amino acid sequence of 175 E proteins representing the different genotypes of DENV3 and identified a panel of surface exposed amino acids, including residues in EDIII, that are highly variant across the four DENV3 genotypes. The variable amino acids include six residues at the lateral ridge of EDIII. We used a panel of DENV3 mouse MAbs to assess the functional significance of naturally occurring amino acid variation. From the panel of antibodies, we identified three neutralizing MAbs that bound to EDIII of DENV3. Recombinant proteins and naturally occurring variant viruses were used to map the binding sites of the three MAbs. The three MAbs bound to overlapping but distinct epitopes on EDIII. Our empirical studies clearly demonstrate that the antibody binding and neutralization capacity of two MAbs was strongly influenced by naturally occurring mutations in DENV3. Our data demonstrate that the lateral ridge “type specific” epitope is not conserved between strains of DENV3. This variability should be considered when designing and evaluating DENV vaccines, especially those targeting EDIII.

Intracellular Cytokine Production by Dengue Virus–specific T cells Correlates with Subclinical Secondary Infection

Abstract: Dengue is an important global health problem, and the dengue viruses (DENV) are the most prevalent arthropod-borne viruses in the tropics and subtropics today. There are an estimated 50–100 million DENV infections annually worldwide [1]. The spectrum of disease ranges from subclinical infection to classical dengue fever to the more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). DHF and DSS, characterized by significant plasma leakage and occasionally hemorrhage and shock, account for an estimated half million cases and >20,000 deaths annually [2]. There are 4 distinct serotypes of dengue virus (DENV 1–4); infection with 1 serotype is believed to confer lifelong immunity to that serotype, whereas protective immunity to heterologous serotypes is short-lived, probably on the order of months [3]. One of the unique features of dengue is the role of heterologous infection in disease severity. Both clinical and epidemiological studies have suggested that the immune response plays a major role in the pathogenesis of severe dengue disease. Subsequent infection with a heterologous serotype predisposes patients toward more severe disease; studies in Southeast Asia, done both in the 1980s [4, 5] and more recently [6, 7], have shown that DHF is associated with secondary infection, implying that other mechanisms in addition to viral replication could be the cause of DHF. Pre-existing heterotypic immunity is believed to increase disease severity in secondary DENV infection and, thus, the risk for DHF through 2 broad hypothetical (and not necessarily mutually exclusive) pathways. The Antibody Dependent Enhancement hypothesis proposes that pre-existing heterotypic anti-DENV IgG antibodies acquired during a previous infection can, under certain conditions, facilitate uptake of virus into macrophages and other immune cells through the binding of virus-antibody complexes to Fcγ receptors. The consequent increase in receptor-mediated endocytosis leads to higher viral loads, which in turn, triggers a host inflammatory cascade that leads to DHF [8]. The second hypothesis involves cross-reactive memory T cells, which are activated during heterologous secondary infection. This leads to altered effector responses, including the generation of cytokines that may create an immunologic imbalance in response to infection and, thus, play either a protective or harmful role in the development of sequelae of infection [9]. Our model of T cell–mediated immunopathogenesis of DENV infection postulates that the relative production of vasoactive cytokines by activated dengue-specific memory T lymphocytes influences the severity of dengue illness [10]. To our knowledge, no previous studies have looked at host-immune factors that specifically correlate with subclinical dengue infection. We hypothesized that the memory T cell response generated during primary DENV infection is a major determinant of cytokine production during secondary infection and, therefore, influences the severity of symptoms experienced during secondary infection. Specifically, we predicted that the frequencies of dengue-specific, cytokine-producing T cells in peripheral blood mononuclear cells (PBMCs) obtained before secondary infection would correlate with the severity of disease seen in secondary infection. To address this hypothesis, we tested PBMCs from Thai schoolchildren enrolled in a prospective cohort study [11]. The unique aspects of this study included the prospective scheduled collection and cryopreservation of PBMCs and the active surveillance for all febrile illnesses. This cohort provided an opportunity to study the predictive value of pre-infection cellular immune profiles with disease phenotype after subsequent DENV infection. From PBMCs obtained before secondary infection, we measured dengue-specific CD4+ and CD8+ T cell cytokine responses to dengue antigens to assess whether these responses predicted future disease severity. Because of the short interval between the collection of the baseline and follow-up blood samples, we believe that the frequencies of the DENV-specific cells at baseline reflect, as accurately as is possible in a large-scale prospective cohort, the host immune status with respect to DENV at the time of secondary infection.

Global distribution and environmental suitability for chikungunya virus, 1952 to 2015.

Abstract: Chikungunya fever is an acute febrile illness caused by the chikungunya virus (CHIKV), which is transmitted to humans by Aedes mosquitoes. Although chikungunya fever is rarely fatal, patients can experience debilitating symptoms that last from months to years. Here we comprehensively assess the global distribution of chikungunya and produce high-resolution maps, using an established modelling framework that combines a comprehensive occurrence database with bespoke environmental correlates, including up-to-date Aedes distribution maps. This enables estimation of the current total population-at-risk of CHIKV transmission and identification of areas where the virus may spread to in the future. We identified 94 countries with good evidence for current CHIKV presence and a set of countries in the New and Old World with potential for future CHIKV establishment, demonstrated by high environmental suitability for transmission and in some cases previous sporadic reports. Aedes aegypti presence was identified as one of the major contributing factors to CHIKV transmission but significant geographical heterogeneity exists. We estimated 1.3 billion people are living in areas at-risk of CHIKV transmission. These maps provide a baseline for identifying areas where prevention and control efforts should be prioritised and can be used to guide estimation of the global burden of CHIKV.