What was special about ZIKV?
Although it was first identified in 1947, the world first came to be aware of Zika virus (ZIKV) during the 2015 epidemics in South America, where 1.5 million people were infected, and a surge of cases of microcephaly and congenital Zika syndrome (CZS) were recorded. Since then, the scientific community has been attempting to answer some pressing questions; how does ZIKV cause microcephaly and CZS? Was there anything special about this epidemic – a mutation in the virus itself, a coincidental co-factor – to explain why, for the first time after over 70 years, we are only now taking notice of ZIKV? Moreover, should we expect further bad surprises from other emerging and re-emerging flaviviruses?
Two interesting studies came to our attention this week, one from Nature communications looking at genetic co-factors that can explain why some ZIKV infections during pregnancy lead to CZS and others do not; the second from Science Translational Medicine looking at whether congenital infections are unique to ZIKV or can occur for other neurotropic flaviviruses.
Is it us or is it the virus?
While some studies have suggested that particular mutations in the Brazilian strains of ZIKV are associated with increased fetal pathogenesis, it is now clear that this alone is an insufficient explanation. Caires-Junior et al. start from the interesting observation that CZS only occurs in 6–12% of children born from infected women, and even more interestingly, while monozygotic twins seem to be equally affected (or not affected by CZS), dizygotic twins are often affected differently. Strikingly, of the seven pairs of dizygotic twins included in the study, six pairs were differently affected (i.e., only one twin born with CZS).
Whole-exome sequence analysis revealed no alterations in genes related to Mendelian inherited microcephaly and only minor differences in more rare variants. Neural progenitor cells (NPCs) from CSZ-affected twins produced higher viral titers after infection and proliferated less. Interestingly, RNA-seq from the same cells before infection identified 64 differentially expressed genes, all involved in the central nervous system and embryonic development. The most significant of these expression differences seem to converge on cellular pathways involved in cell growth and differentiation, including mTOR and Wnt. DDIT4L, an inhibitor of mTOR, is particularly down-regulated in CZS twins. The role of mTOR in ZIKV infection is not clear, with different studies reporting different and contrasting results, but there might be something important in how deregulation of this tightly controlled signaling pathway during development can affect both viral titers and disease.
What controls differential activation of these genes and pathways in dizygotic twins, and whether the genetic differences in rare variants can explain how these pathways respond to infection will require further investigation.
ZIKV only?
The reason why ZIKV has been associated with CZS and microcephaly while other well-known neurotropic flaviviruses like West Nile virus (WNV) haven’t, could just be down to numbers. Platt et al. suggest that larger epidemics might be needed to make the association between maternal infection and fetal disease noticeable and significant. Indeed, congenital infections in humans have also been documented for WNV, Japanese encephalitis virus, and yellow fever virus. In the attempt to understand whether these flaviviruses are also associated with microcephaly and neurodevelopmental problems, Platt and colleagues studied WNV and Powassan virus infection in immunocompetent mice and compared this to infection with alphaviruses, for which the associations with congenital infection is much weaker or not reported. These authors detected higher levels of viral replication and fetal damage upon infection with WNV than with alphaviruses, despite equal viral levels in the mother’s blood. Explants from human maternal and fetal tissue show similar results, with higher WNV replication in chorionic villi and maternal decidua, and more severe fetal damage, suggesting that flaviviruses are associated with congenital syndromes.
Modeling a flavivirus infection in a mouse model is challenging because these models mostly fail to recapitulate human disease. The ability of these viruses to modulate immune response is also different in the two species; so that what is likely to be the major player in infection control is not accurately accounted for. Equally, human tissue explants cannot recapitulate the ability of the organism to control infection, making it difficult to extrapolate conclusions. However, this study suggests that there could be something different about certain flaviviruses that expose the host to a higher risk of congenital transmission and tissue damage. Whether this is down to tropism, route of transplacental transmission, immune response, or – most likely – a combination of interlinked virological, genetic, and environmental factors (what is the impact, for instance, of co-circulation and previous exposure to other arboviruses?) is another challenging question that further highlights the complexity of this long-neglected group of viruses.
