First experimental in vivo model of enhanced dengue disease severity through maternally acquired heterotypic dengue antibodies.
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.
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Jowin Kai Wei
JK
Ng
Defence Science Organization National Laboratories, Singapore.
Summer Lixin
SL
Zhang
Progamme in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Hwee Cheng
HC
Tan
Department of Pathology, National University Health System and National University of Singapore, Singapore.
Benedict
B
Yan
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Julia Maria
JM
Martinez
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Wei Yu
WY
Tan
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Jian Hang
JH
Lam
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Grace Kai Xin
GK
Tan
Progamme in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Eng Eong
EE
Ooi
Department of Microbiology, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore; Immunology Programme, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, Singapore.
Sylvie
S
Alonso
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D006224:Cricetinae; D003429:Cross Reactions / Q000276:immunology; D003715:Dengue / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007112:Immunity, Maternally-Acquired; D051379:Mice; D008817:Mice, Mutant Strains; D011247:Pregnancy; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000914:Antibodies, Viral; D014409:Tumor Necrosis Factor-alpha