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How age contributes to severe POWV encephalitis remains an enigma, and no animal models have assessed age-dependent POWV neuropathology. Inoculating C57BL\/6 mice with a POWV strain (LI9) currently circulating in\n              <jats:italic>Ixodes<\/jats:italic>\n              ticks resulted in age-dependent POWV lethality 10\u201320 dpi. POWV infection of 50-week-old mice was 82% fatal with lethality sequentially reduced by age to 7.1% in 10-week-old mice. POWV LI9 was neuroinvasive in mice of all ages, causing acute spongiform CNS pathology and reactive gliosis 5\u201315 dpi that persisted in survivors 30 dpi. High CNS viral loads were found in all mice 10 dpi. However, by 15 dpi, viral loads decreased by 2\u20134 logs in 10- to 40-week-old mice, while remaining at high levels in 50-week-old mice. Age-dependent differences in CNS viral loads 15 dpi occurred concomitantly with striking changes in CNS cytokine responses. In the CNS of 50-week-old mice, POWV induced Th1-type cytokines (IFN\u03b3, IL-2, IL-12, IL-4, TNF\u03b1, IL-6), suggesting a neurodegenerative pro-inflammatory M1 microglial program. By contrast, in 10-week-old mice, POWV-induced Th2-type cytokines (IL-10, TGF\u03b2, IL-4) were consistent with a neuroprotective M2 microglial phenotype. These findings correlate age-dependent CNS cytokine responses and viral loads with POWV lethality and suggest potential neuroinflammatory therapeutic targets. Our results establish the age-dependent lethality of POWV in a murine model that mirrors human POWV severity and long-term CNS pathology in the elderly.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Powassan virus is an emerging tick-borne flavivirus causing lethal encephalitis in aged individuals. We reveal an age-dependent POWV murine model that mirrors human POWV encephalitis and long-term CNS damage in the elderly. We found that POWV is neuroinvasive and directs reactive gliosis in all age mice, but at acute stages selectively induces pro-inflammatory Th1 cytokine responses in 50-week-old mice and neuroprotective Th2 cytokine responses in 10-week-old mice. Our findings associate CNS viral loads and divergent cytokine responses with age-dependent POWV lethality and survival outcomes. Responses of young mice suggest potential therapeutic targets and approaches for preventing severe POWV encephalitis that may be broadly applicable to other neurodegenerative diseases. Our age-dependent murine POWV model permits analysis of vaccines that prevent POWV lethality, and therapeutics that resolve severe POWV encephalitis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00560-24","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T13:03:03Z","timestamp":1722517383000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Age-dependent Powassan virus lethality is linked to glial cell activation and divergent neuroinflammatory cytokine responses in a murine model"],"prefix":"10.1128","volume":"98","author":[{"given":"Megan C.","family":"Mladinich","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E.","family":"Himmler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas N.","family":"Conde","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena E.","family":"Gorbunova","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Schutt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayan","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Styliani-Anna E.","family":"Tsirka","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2095-9705","authenticated-orcid":true,"given":"Hwan Keun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9156-1222","authenticated-orcid":true,"given":"Erich R.","family":"Mackow","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Center for Infectious Disease, Stony Brook, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0714-0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00106-17"},{"key":"e_1_3_3_4_2","first-page":"708","article-title":"Powassan virus: isolation of virus from a fatal case of encephalitis","volume":"80","author":"McLean DM","year":"1959","unstructured":"McLeanDM, DonohueWL. 1959. 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