Authors: Maïlis Darmuzey, Franck Touret, Emily Slowikowski, Ivan Gladwyn-Ng, Karan Ahuja, Lorena Sanchez-Felipe, Xavier de Lamballerie, Catherine Verfaillie, Pedro E. Marques, Johan Neyts & Suzanne J. F. Kaptein
Nature Communications volume 15, Article number: 10870 (2024)
ABSTRACT
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.
INTRODUCTION
The Zika virus (ZIKV) was first discovered in 1947 during a yellow fever surveillance study amongst monkeys in the Zika forest. During the 1950’s and 1960’s, ZIKV has circulated in human populations in Africa and the Asian-Pacific regions, as evidenced by the detection of antibodies in humans and its first isolation from a human1, causing only sporadic outbreaks associated with no or only mild symptomatic cases2. As a result, ZIKV was not considered a major health threat. However, between 2015 and 2016, ZIKV caused a massive outbreak in the Americas that was associated with an increased number of newborns with congenital Zika syndrome (CZS)3, which encompasses a wide spectrum of birth defects, including microcephaly (smaller skull size), ventriculomegaly (enlarged ventricles), calcification of subcortical regions, neurologic impairment, ocular anomalies, and joint contractures4,5. The emergence of these unprecedented ZIKV-associated devastating neonatal abnormalities led the World Health Organization (WHO) to declare the 2015-ZIKV outbreak a public health emergency of international concern. Since then, various research groups have explored the underlying pathophysiological mechanisms that may explain the high neurovirulence of contemporary ZIKV strains. ZIKV has been reported to be able to infect various cell types in the brain (in vitro and in vivo), such as neural progenitors6,7,8,9,10, mature neurons6,11, astrocytes12,13,14,15,16, oligodendrocytes17,18,19, and microglia20,21,22,23. ZIKV infection of brain cells can induce various deleterious effects, including cell death7,9,24,25, premature differentiation of neural progenitors26,27,28, and secretion of inflammatory factors20,29,30, which could ultimately lead to the development of a microcephaly-like phenotype. Although these studies provided very important insights into the pathophysiological mechanisms underlying ZIKV-associated brain defects, the question on this precipitous emergence remained unanswered. The sudden increase in cases of CZS were linked to ZIKV from the Asian lineage31, which had evolved from the ancestral African lineage32. Several research groups demonstrated that ZIKV from both the African and Asian lineage is equally capable of infecting the placenta33,34 and brain cells35,36,37. Intriguingly, ZIKV from the African lineage was reported to display a more pathogenic profile than ZIKV from the Asian lineage, making it more likely to be associated with miscarriages and spontaneous abortions than with birth defects35,36,38,39,40. Several studies aimed to identify potential genetic determinants of the sudden emergence of ZIKV-associated brain defects caused by the Asian lineage ZIKV41,42,43,44,45, but these yielded conflicting results35,36,41,43. Moreover, some point mutations that were reported to affect the virulence of a particular ZIKV strain did not result in the same effect in the background of other ZIKV strains46. The explanation for the discrepancies in the reported findings is likely multifactorial, such as the use of different mouse models, inoculums, routes of infection, and ZIKV strains, amongst others, increasing the variability in the neurovirulence findings and complicating direct comparisons across studies. […]
