Abstract
Dengue (DEN) represents the most serious arthropod-borne viral disease. DEN clinical manifestations range from mild febrile illness to life-threatening hemorrhage and vascular leakage. Early epidemiological observations reported that infants born to DEN-immune mothers were at greater risk to develop the severe forms of the disease upon infection with any serotype of dengue virus (DENV). From these observations emerged the hypothesis of antibody-dependent enhancement (ADE) of disease severity, whereby maternally acquired anti-DENV antibodies cross-react but fail to neutralize DENV particles, resulting in higher viremia that correlates with increased disease severity. Although in vitro and in vivo experimental set ups have indirectly supported the ADE hypothesis, direct experimental evidence has been missing. Furthermore, a recent epidemiological study has challenged the influence of maternal antibodies in disease outcome. Here we have developed a mouse model of ADE where DENV2 infection of young mice born to DENV1-immune mothers led to earlier death which correlated with higher viremia and increased vascular leakage compared to DENV2-infected mice born to dengue naïve mothers. In this ADE model we demonstrated the role of TNF-α in DEN-induced vascular leakage. Furthermore, upon infection with an attenuated DENV2 mutant strain, mice born to DENV1-immune mothers developed lethal disease accompanied by vascular leakage whereas infected mice born to dengue naïve mothers did no display any clinical manifestation. In vitro ELISA and ADE assays confirmed the cross-reactive and enhancing properties towards DENV2 of the serum from mice born to DENV1-immune mothers. Lastly, age-dependent susceptibility to disease enhancement was observed in mice born to DENV1-immune mothers, thus reproducing epidemiological observations.Overall, this work provides direct in vivo demonstration of the role of maternally acquired heterotypic dengue antibodies in the enhancement of dengue disease severity and offers a unique opportunity to further decipher the mechanisms involved.
Highlights
Dengue (DEN) is the most prevalent arthropod-borne viral infection in the world [1]
Epidemiological observations indicate that infants born to dengue immune mothers are at greater risk to develop the severe form of the disease (DHF/DSS) upon infection with any serotype of dengue virus (DENV)
It was proposed that the presence of maternally acquired DENV specific antibodies cross react but fail to neutralize DENV particles, resulting in higher viremia that correlates with increased disease severity
Summary
Dengue (DEN) is the most prevalent arthropod-borne viral infection in the world [1]. Approximately 3 billion people who are living in the tropical and subtropical regions from Southeast Asia, the Pacific and the Americas are at risk of infection [1,2,3]. A recent meta-analysis using cartographic approaches estimates 390 million dengue infections per year including 96 million with clinical manifestations [4]. This number is more than three times higher than the previous dengue burden estimated by the World Health Organization [5]. DENV is an enveloped virus with a singlestranded, positive-sense 10.7 kb RNA genome. It is translated as a single polyprotein that is cleaved by viral and host proteases into three structural proteins (capsid [C], pre-membrane/membrane [prM/M] and envelope [E], and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [6]. The virus is primarily transmitted to humans by the highly urbanised Aedes aegypti female mosquito which has spread globally due to increased trade and travel [7]
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