Emerging orthobunyaviruses associated with CNS disease

The Orthobunyavirus genus comprises a wide range of arthropod-borne viruses which are prevalent worldwide and commonly associated with central nervous system (CNS) disease in humans and other vertebrates. Several orthobunyaviruses have recently emerged and increasingly more will likely do so in the future. Despite this large number, an overview of these viruses is currently lacking, making it challenging to determine importance from a One Health perspective. Causality is a key feature of determining importance, yet classical tools are unfit to evaluate the causality of orthobunyaviral CNS disease. Therefore, we aimed to provide an overview of orthobunyaviral CNS disease in vertebrates and objectify the causality strength of each virus. In total, we identified 27 orthobunyaviruses described in literature to be associated with CNS disease. Ten were associated with disease in multiple host species of which seven included humans. Seven viruses were associated with both congenital and postnatal CNS disease. CNS disease-associated orthobunyaviruses were spread across all known Orthobunyavirus serogroups by phylogenetic analyses. Taken together, these results indicate that orthobunyaviruses may have a common tendency to infect the CNS of vertebrates. Next, we developed six tailor-made causality indicators and evaluated the causality strength of each of the identified orthobunyaviruses. Nine viruses had a 'strong' causality score and were deemed causal. Eight had a 'moderate' and ten a 'weak' causality score. Notably, there was a lack of case-control studies, which was only available for one virus. We, therefore, stress the importance of proper case-control studies as a fundamental aspect of proving causality. This comprehensible overview can be used to identify orthobunyaviruses which may be considered causal, reveal research gaps for viruses with moderate to low causality scores, and provide a framework to evaluate the causality of orthobunyaviruses that may newly emerge in the future. Author summary Orthobunyaviruses are commonly implicated as causes of CNS disease. Well known examples include La Crosse virus, the primary cause of encephalitis in children in the United States, and Schmallenberg virus, responsible for causing large outbreaks of CNS defects in newborn ruminants in Europe and Asia. In addition, several other less-known and novel orthobunyaviruses have also been implicated in CNS disease, yet association does not imply causality. Considering that nearly one hundred orthobunyaviruses are known to date and more are discovered every year, it is important to determine which orthobunyaviruses are relevant in the context of CNS disease, yet an overview of such information was lacking. To solve this problem, we first identified all orthobunyaviruses associated with CNS disease in literature and subsequently-given that the classical causality indicators are unfit for orthobunyaviral CNS disease-evaluated the strength of causality for each virus using tailor-made causality indicators. The results provide a comprehensible overview of orthobunyaviral CNS disease which can be used to guide future research.