Extract from <i>Aphloia theiformis</i>, an edible indigenous plant from Reunion Island, impairs Zika virus attachment to the host cell surface

International audienceThe mosquito-borne Zika virus (ZIKV) belongs to the flavivirus genus of the Flaviviridae family. Contemporary epidemic strains of ZIKV are associated with congenital malformations in infants, including microcephaly, as well as Guillain-Barré syndrome in adults. A risk of human-to-human transmission of ZIKV is also well documented. A worldwide research effort has been undertaken to identify safe and effective strategies to prevent or treat ZIKV infection. We show here that extract from Aphloia theiformis, an edible endemic plant from Indian Ocean islands, exerts a potent antiviral effect against ZIKV strains of African and Asian lineages, including epidemic strains. The antiviral effect of A. theiformis extract was extended to clinical isolates of dengue virus (DENV) of the four serotypes in human hepatocytes. A. theiformis inhibited virus entry in host cells by acting directly on viral particles, thus impairing their attachment to the cell surface. Electron microscopic observations revealed that organization of ZIKV particles was severely affected by A. theiformis. We propose a model of antiviral action for A. theiformis against flaviviruses that highlights the potential of medicinal plants as promising sources of naturally-derived antiviral compounds to prevent ZIKV and DENV infections. Zoonotic Zika virus (ZIKV) is a mosquito-borne virus that emerged in 2007 in Micronesia and since has caused important outbreaks in the South Pacific, Americas and SouthEast Asia. These recent ZIKV epidemics were associated with severe fetal brain injuries and neurological defects in adults, such as Guillain-Barre syndrome 1,2. ZIKV infection is now identified as a sexually-transmitted illness as well 3-5. In 2016, Zika infection was declared an emerging epidemic threat worldwide by the World Health Organization. ZIKV is a member of the flavivirus genus, a group of small, enveloped viruses, which also includes Dengue virus (DENV), West Nile virus (WNV) and Yellow fever virus 6. The genome consists of a single-stranded, positive-sense RNA molecule of around 10,7 kb, encoding a polyprotein precursor that is processed by the viral protease NS3 to give rise to 7 non-structural (NS) proteins and 3 structural proteins (Capsid C, pre-membrane prM and Envelope E). The NS proteins are mainly involved in viral RNA replication, while the structural proteins constitute the virion 7,8. The early stages of ZIKV infection require the attachment of the virion to the cell surface. This first step is mainly mediated by the interaction between phosphatidylserine exposed at the surface of the virus and the cellular receptor Axl 9 and probably also mobilizes close contacts between the E protein and the cell membrane. Following Axl mediated-binding, the virus enters target cells through clathrin-mediated endocytosis 9. The low-pH environment of endosomes triggers fusion between the viral envelope and the endosomal membrane. This fusion event leads to the release of the viral nucleocapsid into the cytosol