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Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation.

Overview

Authors: Marcos Romario Matos de Souza1, Marissa R. Lindner1, Megan Mladinich-Valenti2, Elena E. Gorbunova1, Varvara Kirillov1, Aisling G. Byrne1, Autumn Y. Laird1, Catherine E. Finnerty1, Priscila Ikeda1, Charles K. Vorkas1,3, Rimanpreet Kaur1,3, Yago C. P. Gomes4, Laurent Chatel-Chaix4, Hwan Keun Kim1, Erich R. Mackow1
  1. Department of Microbiology and Immunology, Center for Infectious Disease, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
  2. SUNY Old Westbury, Old Westbury, New York, USA
  3. Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
  4. Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Quebec, Canada
Institutions: Stony Brook University (United States); SUNY Old Westbury (United States); Institut National de la Recherche Scientifique (Canada)
Journal: mBio, volume 17, issue 8, pages e01294-26
Dates: received 26 May 2026; accepted 10 June 2026; published online 14 July 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1128/mbio.01294-26 · PMID 42446869 · PMCID PMC13464003 · OpenAlex W7168264070
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: genetics / omics (modality), human (organism), mouse (organism), other condition (population), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Smoothing, state filtering, decompositions
Keywords: Powassan virus, neurovirulence, amyloid precursor protein, microglial activation, single-cell RNA-seq, age-dependent, cerebral cortex, TREM2, ApoE, murine model, Alzheimer's-like
MeSH: Alzheimer Disease*, Amyloid beta-Peptides*, Amyloid beta-Protein Precursor*, Brain*, Neuroinflammatory Diseases*, Age Factors, Aging, Animals, Disease Models, Animal, Encephalitis, Viral, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Microglia, Receptors, Immunologic, Single-Cell Analysis, Single-Cell Gene Expression Analysis (* major topic)
Topic: Mosquito-borne diseases and control (Public Health, Environmental and Occupational Health, Medicine), according to OpenAlex
Funding: National Institute of Allergy and Infectious Diseases (NIAID) (R01AI179817, RO1AI183762, R21AI180288, R61AI179732, R01AI152208, R21AI171578, R21AI83259, R21AI96576); U.S. Department of Defense (DOD) (W81XWH2210702, HT94252410378); Fonds de Recherche du Québec – Santé (FRQS) (330358, 370123)
Citations: not cited yet (Europe PMC); 134 references in the paper

Abstract

Powassan virus (POWV) causes lethal encephalitis in the elderly and long-term neurological sequelae in survivors. Mirroring human disease, POWV strain LI9 directs age-dependent lethality in C57BL/6 (B6) mice, resulting in spongiform encephalitis, gliosis, and inflammatory cytokine/chemokine responses in the CNS. However, the mechanisms underlying age-dependent lethality and persistent neurodegenerative disease in POWV survivors remain to be resolved. Here, we analyzed cellular CNS responses to POWV LI9 infection in young (10-week-old) and aged (50-week-old) mice using single-cell RNA sequencing. Infection of young mice resulted in inflammatory CNS infiltrates (NK, CD4/CD8 T cells, and monocytes) and interferon responses that coincide with peak viral burden. In contrast, the CNS of aged infected mice instead featured upregulated astrocyte and neuronal genes associated with neurodegenerative and Alzheimer’s disease pathways and the transition of homeostatic microglia to a Trem2–ApoE-linked disease-associated microglial transcriptional state. Histological analysis revealed that amyloid precursor protein (APP)/amyloid-β (Aβ) accumulated in the CNS following POWV infection and that POWV envelope protein and APP/Aβ were selectively localized within layers L5/L6 of the cerebral cortex. POWV kinetically increased perinuclear APP/Aβ accumulation during acute infection and was highly expressed in the CNS of POWV survivors. Our findings reveal that POWV triggers glial cell responses and a neurodegenerative disease-associated microglia program of Alzheimer’s-like APP/Aβ accumulation in mice, which is consistent with long-term neurological sequelae in human POWV survivors.

IMPORTANCE: Powassan virus (POWV) causes lethal encephalitis and long-term cognitive deficits in survivors. Using an age-dependent murine model, we reveal that POWV-infected young mice direct robust CNS inflammatory infiltrates associated with viral clearance, whereas aged mice exhibit impaired immune responses and a shift from homeostatic to neurodegenerative glial cell states. POWV prompted the induction of disease-associated microglia (DAM) and Trem2–ApoE axis transcriptional responses that are hallmarks of APP/amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Remarkably, POWV induced progressive APP/Aβ accumulation in young and aged mice that persisted in survivors after viral clearance. This suggests that POWV induces an APP/Aβ neurodegenerative process and provides a potential cause of long-term neurological sequelae observed in human POWV survivors. Our data suggest that POWV initiates or exacerbates AD-like neuropathology and further rationalizes investigating the role of APP/Aβ responses in other encephalitic viruses.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

Complete methods underlying this study are provided in the Supplemental Methods. scRNA-seq data have been deposited in NCBI GEO under accession number GSE329199 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329199), including raw FASTQ files, processed expression matrices, and cell-level metadata. Custom analysis scripts are available by request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 11 keywords, 17 MeSH terms, 3 funders, 134 references.

Cite

This paper

de Souza, M. R. M., Lindner, M. R., Mladinich-Valenti, M., Gorbunova, E. E., Kirillov, V., Byrne, A. G., Laird, A. Y., Finnerty, C. E., Ikeda, P., Vorkas, C. K., Kaur, R., Gomes, Y. C. P., Chatel-Chaix, L., Kim, H. K., & Mackow, E. R. (2026). Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation. mBio, 17(8), e01294-26. https://doi.org/10.1128/mbio.01294-26

BibTeX

@article{desouza2026single,
author = {de Souza, Marcos Romario Matos and Lindner, Marissa R. and Mladinich-Valenti, Megan and Gorbunova, Elena E. and Kirillov, Varvara and Byrne, Aisling G. and Laird, Autumn Y. and Finnerty, Catherine E. and Ikeda, Priscila and Vorkas, Charles K. and Kaur, Rimanpreet and Gomes, Yago C. P. and Chatel-Chaix, Laurent and Kim, Hwan Keun and Mackow, Erich R.},
title = {{Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation}},
journal = {mBio},
year = {2026},
month = jul,
volume = {17},
number = {8},
pages = {e01294--26},
publisher = {American Society for Microbiology (ASM)},
issn = {2150-7511},
doi = {10.1128/mbio.01294-26},
url = {https://doi.org/10.1128/mbio.01294-26},
pmid = {42446869},
pmcid = {PMC13464003}
}

RIS

TY - JOUR
AU - de Souza, Marcos Romario Matos
AU - Lindner, Marissa R.
AU - Mladinich-Valenti, Megan
AU - Gorbunova, Elena E.
AU - Kirillov, Varvara
AU - Byrne, Aisling G.
AU - Laird, Autumn Y.
AU - Finnerty, Catherine E.
AU - Ikeda, Priscila
AU - Vorkas, Charles K.
AU - Kaur, Rimanpreet
AU - Gomes, Yago C. P.
AU - Chatel-Chaix, Laurent
AU - Kim, Hwan Keun
AU - Mackow, Erich R.
TI - Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation
T2 - mBio
J2 - mBio
PY - 2026
DA - 2026/07/14
VL - 17
IS - 8
SP - e01294
EP - 26
SN - 2150-7511
PB - American Society for Microbiology (ASM)
DO - 10.1128/mbio.01294-26
UR - https://doi.org/10.1128/mbio.01294-26
LA - en
ER -

CSL-JSON

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