SARS-CoV-2 post-acute sequelae linked to inflammation via extracellular vesicles

Sara Bachiller ^1* Joana Vitalle ² Lluís Camprubí-Ferrer ³ Manuel García ⁴ Isabel Gallego ² Marina López-García ⁵ María Isabel Galvá ⁶ Julio Cañizares ⁶ Inmaculada Rivas-Jeremías ² María Díaz-Mateos ⁷ Carmen Gasca-Capote ² Cristina Moral-Turón ² Lourdes Galán- Villamor ⁴ María Fontillón ⁴ Salvador Sobrino ⁴ José Miguel Cisneros ² Luis F. Lopez-Cortes ² Tomas Deierborg ³ Ezequiel Ruiz-Mateos ^2*

• ¹ Faculty of Medicine, University of Seville, Seville, Spain
• ² Institute of Biomedicine of Seville, IBiS/Virgen del Rocío University Hospital/CSIC/University of Seville., Seville, Spain
• ³ Lund University, Lund, Skane County, Sweden
• ⁴ Virgen del Rocío University Hospital, Seville, Spain
• ⁵ Bermejales Physiotherapy Clinic, Seville, Spain
• ⁶ Heliopolis Nursing Home, Seville, Spain
• ⁷ Virgen Macarena University Hospital, Seville, Spain

Background: Despite the efficacy of SARS-CoV-2 vaccines in reducing mortality and severe cases of COVID-19, a significant proportion of survivors experience long-term symptoms, known as postacute sequelae of SARS-CoV-2 infection (PASC). This study investigates the long-term immunological and neurodegenerative effects associated with extracellular vesicles (EVs) in COVID-19 survivors, 15 months after SARS-CoV-2 infection.Methods: 13 healthy donors (HD)Controls and 20 COVID-19 survivors, 15 months after SARS-CoV-2 infection, were recruited. Proinflammatory cytokines were analyzed in both plasma and EVs. A deep-immunophenotyping of monocytes, T-cells and dendritic cells (DCs) was performed, along with immunostainings of SARS-CoV-2 in the colon.Results: Higher concentrations of proinflammatory cytokines and neurofilaments were found in EVs but not in plasma from COVID-19 survivors. Additionally, COVID-19 participants exhibited altered monocyte activation markers and elevated cytokine production upon lipopolysaccharide (LPS) stimulation. Increased activation markers in CD4+ T-cells and decreased indoleamine 2,3-dioxygenaseIDO expression in DCs were observed in COVID-19 participants. Furthermore, the levels amount of plasmacytoid DCs (pDCs) expressing β7-integrin were higher in COVID-19, potentially associated with the viral persistence observed in the colon.Conclusions: COVID-19 survivors exhibit long-term immune dysregulation and neurodegeneration, emphasizing the need for ongoing monitoring of PASC. The cargo of EVs seems tocan be a promising tool for early detection of virus-induced neurological disorders.