The 2015-2016 Zika virus (ZIKV) outbreak in the Americas revealed the ability of ZIKV from the Asian lineage to cause birth defects, generically called congenital Zika syndrome (CZS). Notwithstanding the long circulation history of Asian ZIKV, no ZIKV-associated CZS cases were reported prior to the outbreaks in French Polynesia (2013) and Brazil (2015). Whether the sudden emergence of CZS resulted from an evolutionary event of Asian ZIKV has remained unclear. We performed a comparative analysis of the pathogenicity of pre-epidemic and epidemic Asian ZIKV strains in mouse embryonic brains using a female immunocompetent intraplacental infection mouse model. All studied Asian ZIKV strains are neurovirulent, but pre-epidemic strains are consistently more pathogenic in the embryos than their epidemic equivalents. Pathogenicity is not directly linked to viral replication. By contrast, an influx of macrophages/microglial cells is noted in infected fetal brains for both pre-epidemic and epidemic ZIKV strains. Moreover, all tested ZIKV strains trigger an immunological response, whereby the intensity of the response differs between strains, and with epidemic ZIKV strains generally mounting a more attenuated immunostimulatory response. Our study reveals that Asian ZIKV strains evolved towards pathogenic attenuation, potentially resulting in CZS emergence in neonates rather than premature death in utero.

The global emergence of Zika virus (ZIKV) revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects. A puzzling aspect of ZIKV emergence is that all human outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compare seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We find that recent African ZIKV strains display higher transmissibility in mosquitoes and higher lethality in both adult and fetal mice than their Asian counterparts. We emphasize the high epidemic potential of African ZIKV strains and suggest that they could more easily go unnoticed by public health surveillance systems than Asian strains due to their propensity to cause fetal loss rather than birth defects.

Summary The global emergence of Zika virus (ZIKV) in the last decade revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects such as microcephaly. A puzzling aspect of ZIKV emergence is that all human outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compared the transmissibility and pathogenicity of seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We found that recent African ZIKV strains largely outperformed their Asian counterparts in mosquito transmission kinetics experiments, which translated into a markedly higher epidemic potential in outbreak computer simulations. In addition, African ZIKV strains were significantly more lethal than Asian ZIKV strains in immunocompromised adult mice. Finally, prenatal infection of immunocompetent mouse embryos with an African ZIKV strain resulted in embryonic death whereas it caused microcephaly with Asian ZIKV strains. Together, our results demonstrate the high epidemic potential and pathogenicity of recent ZIKV strains from Africa. Importantly, they also imply that the African ZIKV lineage could more easily go unnoticed by public health surveillance systems than the Asian ZIKV lineage due to its propensity to cause fetal loss rather than birth defects.