Comparative pathogenesis of two lineages of Powassan virus reveals differing routes of neuroinvasion leading to distinct clinical outcome, neuropathology and inflammation

Abstract

Tick-borne flaviviruses (TBFV) can cause severe neuroinvasive disease which may result in death or long-term neurological deficit in over 50% of survivors. Multiple mechanisms for invasion of the central nervous system (CNS) by flaviviruses have been proposed including axonal transport, transcytosis, endothelial infection, and Trojan horse routes. Flaviviruses may utilize different or multiple mechanisms of neuroinvasion depending on the specific virus, infection site, and host variability. In this work we have shown that infection of BALB/cJ mice with either Powassan virus lineage I (Powassan virus) or lineage II (deer tick virus) results in distinct spatial tropism of infection in the CNS which correlated with unique clinical presentation for each lineage. Comparative transcriptomics of infected brains demonstrates activation of different immune pathways and downstream host responses. Ultimately the comparative pathology and transcriptomics are congruent with different clinical signs in a murine model. These results suggest that different disease presentations would be occur in clinical cases due to the innate differences in the two lineages of Powassan virus. Author SummaryPowassan virus causes a nationally notifiable disease which can cause severe neurological disease in humans and has no approved vaccines or therapeutics. Although two distinct lineages circulate in North America, clinical differentiation is not typically performed, and pathology has been assumed to be similar between lineages. In this work, a direct comparison of lineage I (Powassan virus) and lineage II (deer tick virus) demonstrated distinct differences in the clinical presentation, pathology of the central nervous system, and immune response in immunocompetent mice. These differences suggest that deer tick virus and Powassan virus do not utilize the same mechanisms for neuroinvasion and dissemination within the CNS. This is clinically relevant as the development of treatment plans and therapeutics need to be evaluated for these virus lineages.