Of murines and humans: Modeling persistent Powassan disease in C57BL/6 mice

Authors: Scroggs, Stacey; OFFERDAHL, DANIELLE - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); STEWART, PHILIP - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); SHAIA, CARL - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); GRIFFIN, AMANDA - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH); BLOOM, MARSHALL - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)

Submitted to: mBio
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2023
Publication Date: 2/21/2023
Citation: Scroggs, S.L., Offerdahl, D.K., Stewart, P.E., Shaia, C., Griffin, A.J., Bloom, M.E. 2023. Of murines and humans: Modeling persistent Powassan disease in C57BL/6 mice. mBio. Article e03606-22. https://doi.org/10.1128/mbio.03606-22.
DOI: https://doi.org/10.1128/mbio.03606-22

Interpretive Summary: Half of Powassan infection survivors will experience long-term, mild to severe neurological symptoms. The progression from acute to chronic Powassan disease is not well understood, severely limiting treatment and prevention options. C57BL/6 mice infected with DTV mimic clinical disease in humans and exhibit CNS inflammation and viral RNA persistence until at least 86 dpi, while infectious virus is undetectable after 21 dpi. These findings suggest that the long-term neurological symptoms of chronic Powassan disease are in part due the persistence of viral RNA and the corresponding long-term inflammation of the brain and spinal cord. Our work demonstrates that C57BL/6 mice can be used to study the pathogenesis of chronic Powassan disease.

Technical Abstract: Powassan infection is caused by two closely related, tick-transmitted viruses of the genus Flavivirus (family Flaviviridae): Powassan virus lineages I (POWV) and II (also known as deer tick virus (DTV)). Infection is typically asymptomatic or mild, but can progress to neuroinvasive disease. Approximately 10% of neuroinvasive cases are fatal and half of the survivors will experience long-term neurological sequelae. Understanding how these viruses cause long-term symptoms as well as the possible role of viral persistence is important for developing therapies to treat chronic infection. We inoculated six-week-old C57BL/6 mice with DTV and assayed for infectious virus, viral RNA, and inflammation during the acute phase of infection, and 21, 56, and 84 days post infection (dpi) in central nervous system (CNS) and non-CNS tissues. Although most mice (86%) were viremic 3 dpi, only 21% of the mice were symptomatic and 83% recovered. Infectious virus was only detected in the brains of mice sampled during the acute infection. The distribution of genomic viral RNA in the brain and spinal cord was more widespread in mice sampled during the acute infection; viral RNA was detected in the brain until 84 dpi, but the magnitude decreased by time. Meningitis and encephalitis were visible in acute mice and from mice sampled at 21 dpi but were significantly more severe in the former. Long-term inflammation was observed until 56 dpi in the brain and 84 dpi in the spinal cord, albeit at low levels. Together these results suggest that the long-term neurological symptoms associated with Powassan disease are likely caused by lingering viral RNA and chronic inflammation in the central nervous system rather than by a persistent, active viral infection. Additionally, the level of viremia early in infection did not correlate with progression to persistent disease. The C57BL/6 model of persistent Powassan mimics illness in humans and can be used to study the mechanisms of chronic disease and test potential treatments to alleviate disease burden.