Research Article: First Experimental In Vivo Model of Enhanced Dengue Disease Severity through Maternally Acquired Heterotypic Dengue Antibodies

Date Published: April 3, 2014

Publisher: Public Library of Science

Author(s): Jowin Kai Wei Ng, Summer Lixin Zhang, Hwee Cheng Tan, Benedict Yan, Julia Maria Martinez Gomez, Wei Yu Tan, Jian Hang Lam, Grace Kai Xin Tan, Eng Eong Ooi, Sylvie Alonso, Michael S. Diamond.


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.

Partial Text

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]–[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]. With no licensed drug or vaccine, DEN represents a serious public health concern and economic burden for societies.

Advancement in understanding DEN pathogenesis has been largely hampered by the lack of a suitable animal model. Humans and mosquitoes are so far the only known natural hosts for DENV. Upon DENV infection, non-human primates develop viremia and produce neutralizing antibody responses, but they do not display overt clinical signs of disease [11]. Moreover ethic and economic considerations have greatly limited the use of non-human primates as animal model to study DEN. Immune competent mice are not susceptible to DENV infection [11]. Indeed, while DENV was shown to interfere and block IFN signalling in human cells [50], [51], it fails to do so in murine counterparts [52]. Accordingly, immune-compromised mice which lack type I and II IFN signalling pathways (AG129) were found permissive to infection with most of DENV lab strains and clinical isolates whereby transient viremia could be detected [11], [53]. However, clinical manifestations in these mice are DENV strain-dependent and range from none (majority of the DENV strains) to severe vascular leakage accompanied by thrombocytopenia [11]. Recently, our group has reported the subcutaneous infection of adult AG129 mice with a non mouse-adapted DENV2 strain, namely D2Y98P-PP1 [36]. In this model, the virus disseminates systemically and replicates transiently in the blood and a variety of organs. Severe vascular leakage develops over time which eventually leads to non-paralytic death of the infected animals after the virus has been cleared from the blood circulation [36]. However, the lack of functional type I & II IFN responses represents an important weakness for this dengue mouse model since dengue patients are generally immune competent. Data generated in this mouse model must therefore be interpreted with caution, and may not accurately reflect the situation in patients. A recent work has indicated the susceptibility of IFNAR (Type I IFN) KO mice to infection with a DENV2 strain [54]. It would be very interesting to test whether these mice would display maternal antibody-mediated enhancement of disease severity as seen in AG129 mice.




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