Dengue:a growing risk to travellers to tropical and sub-tropical regions

Dengue is op dit moment wereldwijd de meest voorkomende door muggen overgedragen virale infectieziekte.Door de klimaatverandering en andere factoren is het verspreidingsgebied van de vector, de Aedes-mug, de laatste decennia sterk toegenomen.Dengue is endemisch in bijna alle (sub)tropische delen van de wereld; dit betekent dat 40% van de wereldbevolking risico loopt besmet te worden met het denguevirus.Het beloop van dengue kan variëren van een asymptomatische infectie of een ongedifferentieerd ziektebeeld met koorts (klassieke dengue of ‘dengue fever’) tot ernstige, soms fatale, vormen van ziekte zoals hemorragische koorts (‘dengue hemorrhagic fever’, DHF) en het dengue-shocksyndroom (DSS).Gezien de beperkte mogelijkheden van preventie is de verwachting dat de incidentie van dengue de komende jaren verder zal toenemen.Ook in gebieden waar dengue niet endemisch is zullen zorgverleners steeds vaker patiënten met dengue in hun praktijk tegenkomen.Dengue is currently the most common arboviral infection worldwide. Due to global climate change and other factors, the vector of the virus - the Aedes mosquito - has spread considerably over the past decades. Dengue is endemic in almost all tropical and sub-tropical regions of the world; meaning that approximately 40% of the world population is at risk of acquiring a dengue infection. The clinical features of dengue vary from a non-specific febrile illness (dengue fever) to at times fatal serious conditions such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Considering the limited possibilities of prevention it is anticipated that the incidence of dengue will increase in the future. It is expected that health-care providers in non-endemic regions will encounter dengue-infected patients with increasing frequency in their practices.</p

Dengue:a growing risk to travellers to tropical and sub-tropical regions

Dengue is op dit moment wereldwijd de meest voorkomende door muggen overgedragen virale infectieziekte.Door de klimaatverandering en andere factoren is het verspreidingsgebied van de vector, de Aedes-mug, de laatste decennia sterk toegenomen.Dengue is endemisch in bijna alle (sub)tropische delen van de wereld; dit betekent dat 40% van de wereldbevolking risico loopt besmet te worden met het denguevirus.Het beloop van dengue kan variëren van een asymptomatische infectie of een ongedifferentieerd ziektebeeld met koorts (klassieke dengue of ‘dengue fever’) tot ernstige, soms fatale, vormen van ziekte zoals hemorragische koorts (‘dengue hemorrhagic fever’, DHF) en het dengue-shocksyndroom (DSS).Gezien de beperkte mogelijkheden van preventie is de verwachting dat de incidentie van dengue de komende jaren verder zal toenemen.Ook in gebieden waar dengue niet endemisch is zullen zorgverleners steeds vaker patiënten met dengue in hun praktijk tegenkomen.Dengue is currently the most common arboviral infection worldwide. Due to global climate change and other factors, the vector of the virus - the Aedes mosquito - has spread considerably over the past decades. Dengue is endemic in almost all tropical and sub-tropical regions of the world; meaning that approximately 40% of the world population is at risk of acquiring a dengue infection. The clinical features of dengue vary from a non-specific febrile illness (dengue fever) to at times fatal serious conditions such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Considering the limited possibilities of prevention it is anticipated that the incidence of dengue will increase in the future. It is expected that health-care providers in non-endemic regions will encounter dengue-infected patients with increasing frequency in their practices.</p

Immature Dengue Virus Is Infectious in Human Immature Dendritic Cells via Interaction with the Receptor Molecule DC-SIGN

BACKGROUND: Dengue Virus (DENV) is the most common mosquito-borne viral infection worldwide. Important target cells during DENV infection are macrophages, monocytes, and immature dendritic cells (imDCs). DENV-infected cells are known to secrete a large number of partially immature and fully immature particles alongside mature virions. Fully immature DENV particles are considered non-infectious, but antibodies have been shown to rescue their infectious properties. This suggests that immature DENV particles only contribute to the viral load observed in patients with a heterologous DENV re-infection. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we re-evaluated the infectious properties of fully immature particles in absence and presence of anti-DENV human serum. We show that immature DENV is infectious in cells expressing DC-SIGN. Furthermore, we demonstrate that immature dendritic cells, in contrast to macrophage-like cells, do not support antibody-dependent enhancement of immature DENV. CONCLUSIONS/SIGNIFICANCE: Our data shows that immature DENV can infect imDCs through interaction with DC-SIGN, suggesting that immature and partially immature DENV particles may contribute to dengue pathogenesis during primary infection. Furthermore, since antibodies do not further stimulate DENV infectivity on imDCs we propose that macrophages/monocytes rather than imDCs contribute to the increased viral load observed during severe heterotypic DENV re-infections

Immature Dengue Virus: A Veiled Pathogen?

Cells infected with dengue virus release a high proportion of immature prM-containing virions. In accordance, substantial levels of prM antibodies are found in sera of infected humans. Furthermore, it has been recently described that the rates of prM antibody responses are significantly higher in patients with secondary infection compared to those with primary infection. This suggests that immature dengue virus may play a role in disease pathogenesis. Interestingly, however, numerous functional studies have revealed that immature particles lack the ability to infect cells. In this report, we show that fully immature dengue particles become highly infectious upon interaction with prM antibodies. We demonstrate that prM antibodies facilitate efficient binding and cell entry of immature particles into Fc-receptor-expressing cells. In addition, enzymatic activity of furin is critical to render the internalized immature virus infectious. Together, these data suggest that during a secondary infection or primary infection of infants born to dengue-immune mothers, immature particles have the potential to be highly infectious and hence may contribute to the development of severe disease

Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2

Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles

Antibodies against Immature Virions Are Not a Discriminating Factor for Dengue Disease Severity

Humoral immunity plays an important role in controlling dengue virus (DENV) infection. Antibodies (Abs) developed during primary infection protect against subsequent infection with the same dengue serotype, but can enhance disease following secondary infection with a heterologous serotype. A DENV virion has two surface proteins, envelope protein E and (pre)-membrane protein (pr)M, and inefficient cleavage of the prM protein during maturation of progeny virions leads to the secretion of immature and partially immature particles. Interestingly, we and others found that historically regarded non-infectious prM-containing DENV particles can become highly infectious in the presence of E- and prM-Abs. Accordingly, we hypothesized that these virions contribute to the exacerbation of disease during secondary infection. Here, we tested this hypothesis and investigated the ability of acute sera of 30 DENV2-infected patients with different grades of disease severity, to bind, neutralize and/or enhance immature DENV2. We found that a significant fraction of serum Abs bind to the prM protein and to immature virions, but we observed no significant difference between the disease severity groups. Furthermore, functional analysis of the Abs did not underscore any specific correlation between the neutralizing/enhancing activity towards immature DENV2 and the development of more severe disease. Based on our analysis of acute sera, we conclude that Abs binding to immature virions are not a discriminating factor in dengue pathogenesis