Persistent Japanese encephalitis virus infection in fetuses of an amplifying pig host affects virus genetic heterogeneity and drives transcriptional footprints in offspring

Japanese encephalitis virus (JEV) is a significant global health concern. This research reveals that during fetal infection in natural JEV amplifying hosts, pigs, the intrauterine environment can foster the development of new intra-host JEV variants. When pigs are infected with JEV transplacentally and in the fetal stage, virus variants that resemble those found in endemic JEV regions appear.

These JEV genetic differences that form during fetal infection remain in fetal membranes expelled and in offspring. Like those in fetuses, JEV mutations found in fetal membranes and offspring have been reported in the field before. After examining mutations that developed in fetuses and offspring during persistent in utero infection and how well they maintained during cell culture passage, this research suggests the possibility of onward transmission of in utero-emerged JEV variants from infected fetal membranes or offspring.

Being exposed to JEV during fetal life also leaves a distinct molecular signature in the blood cells and tonsils of live offspring. These alterations are linked to epigenetic regulation and memory pathways. In summary, this study sheds new light on JEV biology and pathogenesis in its natural amplifying host, pigs, during pregnancy.

The findings pave the way for further research into pathways connecting fetal infection to offspring, subsequent environmental spread, fetal infection as a source of JEV genetic diversity, and the mechanisms behind molecular footprints and their long-term effects in JEV-affected offspring, such as higher susceptibility to zoonotic pathogens.