Experimental evidence for a high rate of maternal-fetal transmission of dengue virus in the presence of antibodies in immunocompromised mice

Abstract

Summary: Background: Congenital disorders associated with prenatal vertical transmission of Zika virus (ZIKV) is well established since the 2016 outbreak in the Americas. However, despite clinical reports of similar mode of transmission for other flaviviruses such as dengue virus (DENV), the phenomenon has not been experimentally explored. Methods: Pregnant AG129 mice were infected with DENV1 in the presence or absence of enhancing antibodies at different gestational time points. ZIKV was used for comparison. We quantified viral load in fetus and placentas and performed comprehensive gene expression profiling in the maternal (decidua) and fetal portion of placenta separately. Findings: We demonstrate in a laboratory experimental setting that DENV can be transmitted vertically in a gestation stage-dependent manner similar to ZIKV, and this incidence drastically increases in the presence of enhancing antibodies. Interestingly, a high rate of DENV fetal infection occurs even though the placental viral load is significantly lower than that found in ZIKV-infected dams. Comprehensive gene expression profiling revealed DENV infection modulates a variety of inflammation-associated genes comparable to ZIKV in decidua and fetal placenta in early pregnancy. Interpretation: Our findings suggest that the virus-induced modulation of host gene expression may facilitate DENV to cross the placental barrier in spite of lower viral burden compared to ZIKV. This mouse model may serve to identify the host determinants required for the vertical transmission of flaviviruses and develop appropriate countermeasures. Funding: National Medical Research Council/Open Fund Individual Research Grant MOH-000524 (SW), MOH-000086 and OFIRG20nov-0017 (SGV).

Keywords

• Dengue virus
• Pregnant mouse model
• Vertical transmission
• Zika virus
• Placenta
• Decidua