Year: 2025
Type: preprint
Abstract: Males suffer more severe outcomes during acute COVID-19 and a greater proportion of females develop post-acute sequalae of COVID-19 (PASC). To identify mechanisms of PASC, mice were infected with SARS-CoV-2 and viral, inflammatory, and behavioral outcomes were evaluated through 84 days post-infection. Sex differences were not observed in virus replication or persistence of viral RNA in pulmonary or extrapulmonary tissues. After infectious virus clearance, females exhibited persistent deficits in spatial working and recognition memory, and greater frequencies of inflammatory myeloid cells, neuroinflammation, and dysregulated T cells, including Tregs. Sex differences in persistent inflammation and cognitive impairments during PASC were mediated by the presence of two X chromosomes and infection-induced upregulation of the X-linked genes Xist and Tlr7, which was reversed by pharmacological inhibition of TLR7 activity during the PASC phase. Sustained X-linked TLR7-mediated inflammation underlies how the burden of PASC is greater for females and provides a therapeutic target.
Authors: Jennifer A. Liu, Sabal Chaulagain, Xinyi Xie, Patrick S. Creisher, Weizhi Zhong, Tianle Zhang, Maraake Taddese, Karly Shi, Han-Sol Park, Haley Hcnir, Arthur P. Arnold, Ralph S. Baric, Natasha B. Barahona, Elizabeth B. Engler-Chiurazzi, Kevin J. Zwezdaryk, Chloe L. Thio, Ashwin Balagopal, Jack R. Harkema, Elizabeth A. Thompson, Andrew Pekosz, Andrea L. Cox, Sabra L. Klein
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Coupling neuroimaging with CLARITY and single cell genomics to dissect sex differences in the developing brain, The Molecular and Cellular Basis of Infectious Diseases (MCBID) Program, Mechanisms of spontaneous and vaccine mediated hepatitis C virus control to direct rational development of a novel HCV vaccine, The Role of Viral Exposure and Age in Alzheimer's Disease Progression
OpenAlex ID: W4415164105