{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:44:57Z","timestamp":1793151897673,"version":"4.5.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The pathogenesis of post-acute sequelae of SARS-CoV-2 infection (PASC) remains poorly understood, and no effective treatment has been established. Reactivation of latent herpesviruses, particularly human herpesvirus 6B (HHV-6B), has been proposed as a possible contributor to the neuropsychiatric symptoms observed in PASC. SITH-1, a latency-associated protein expressed during HHV-6B reactivation in olfactory bulb astrocytes, induces specific antibody responses that can be detected in peripheral blood. Importantly, SITH-1 has also been identified as a risk factor for depression, suggesting a mechanistic link between HHV-6B reactivation and the development of neuropsychiatric symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We measured serum anti-SITH-1 antibody titers in 156 PASC patients and compared them to healthy controls. In this PASC cohort, neuropsychiatric symptoms were assessed using numerical rating scales. In parallel, we developed a mouse model in which SITH-1 was transiently expressed in the olfactory bulb to assess its impact on brain function and behavior. We also conducted a subgroup analysis of a previously reported randomized clinical trial (RCT) of donepezil, stratifying PASC patients by anti-SITH-1 antibody status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Anti-SITH-1 antibody positivity was observed in 62.8% of PASC patients, a significantly higher proportion than in controls. Seropositive patients exhibited more severe fatigue and depressive symptoms. In the mouse model, SITH-1 expression led to reduced acetylcholine production and depression-like behavior, both of which were ameliorated by donepezil. In the clinical trial subgroup of 73 PASC patients, 71.7% were seropositive for anti-SITH-1 antibodies. Among these individuals, donepezil significantly improved fatigue and depression scores, as measured by the Chalder Fatigue Scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that HHV-6B reactivation in the olfactory bulb, as indicated by anti-SITH-1 antibody titers, may contribute to fatigue and depression in a subset of PASC patients. Donepezil may be effective in this subgroup, and these findings support the use of anti-SITH-1 antibody titers as a companion diagnostic marker for targeted treatment in PASC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1807203","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:35:10Z","timestamp":1780551310000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Donepezil ameliorates fatigue and depression in PASC patients with HHV-6B SITH-1-induced acetylcholine deficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Naomi","family":"Oka","sequence":"first","affiliation":[{"name":"Department of Virology, The Jikei University School of Medicine","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Yokohama City University Hospital","place":["Yokohama, Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Hirahata","sequence":"additional","affiliation":[{"name":"Hirahata Clinic","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azusa","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Virology, The Jikei University School of Medicine","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Yamakawa","sequence":"additional","affiliation":[{"name":"Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University","place":["Takatsuki, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenya","family":"Ie","sequence":"additional","affiliation":[{"name":"Department of General Internal Medicine, Kawasaki Municipal Tama Hospital","place":["Kawasaki, Kanagawa, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadahiro","family":"Goto","sequence":"additional","affiliation":[{"name":"TXP Medical Co. 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