Powassan Virus Neuropathology and Genomic Diversity in Patients With Fatal Encephalitis

• Type of Material: Article
• Authors: Erica Normandin, Broad Institute of MIT & Harvard; Isaac H. Solomon, Brigham & Women's Hospital; Siavash Zamirpour, Broad Institute of MIT & Harvard; Jacob Lemieux, Broad Institute of MIT & Harvard; Catherine A. Freije, Broad Institute of MIT & Harvard; Shibani S. Mukerji, Massachusetts General Hospital; Christopher Tomkins-Tinch, Broad Institute of MIT & Harvard; Daniel Park, Broad Institute of MIT & Harvard; Pardis C. Sabeti, Broad Institute of MIT & Harvard; Anne Piantadosi, Emory University
• Language: English
• Date: 2020-10-01
• Publisher: OXFORD UNIV PRESS INC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/ofid/ofaa392
• Title of Journal or Parent Work: OPEN FORUM INFECTIOUS DISEASES
• Volume: 7
• Issue: 10
• Start Page: ofaa392
• End Page: ofaa392
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) grants R01AI137424 and K08AI139348, by the Howard Hughes Medical Institute (HHMI), and by Defense Advanced Research Projects Agency (DARPA) grant DC18AC00006.
• Keywords: TRANSMISSION; DEER; NUCLEIC-ACID DETECTION; ALIGNMENT; INFECTION; ZIKA VIRUS; Life Sciences & Biomedicine; neuropathology; flavivirus; Infectious Diseases; EVOLUTION; Science & Technology; Microbiology; Immunology; viral genomics; molecular diagnostics
• Research Categories: Biology, Virology; Biology, Microbiology; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

Background. Powassan virus (POWV) is an emerging cause of severe encephalitis; very little is known about human pathogenicity due to challenges in diagnosis and viral RNA recovery. We present 3 patients with fatal encephalitis due to POWV lineage II (deer tick virus). Methods. We obtained 27 unique samples, including from brain biopsy and autopsy, and used metagenomic sequencing, quantitative reverse transcriptase polymerase chain reaction, and a newly developed CRISPR-based diagnostic assay to perform the first detailed characterization of POWV compartmentalization and genomics between and within human subjects. Results. In all 3 patients, imaging and histopathology findings were notable for profound cerebellar involvement. All patients were initially diagnosed with POWV by metagenomic sequencing, and 2 of the 3 had negative clinical testing by serology. We detected POWV RNA in 13 clinical samples; levels were highest in the cerebellum, and there was very little involvement of peripheral tissue. We assembled complete POWV genomes from 8 samples, providing unique information about the strains of POWV lineage II (deer tick virus) that infect humans. Conclusions. We demonstrate the utility of molecular assays for detecting POWV infection, including in seronegative patients, and nominate viral genomic features that may relate to human infection and neuropathogenicity. The cerebellum was identified as a key target POWV in fatal infection, by radiological and histopathological findings as well as molecular testing.