Modulation of TLR7, TYK2 and OAS1 expression during SARS-CoV-2 infection

Estíbaliz Alegría-Carrasco¹Marta Jaén-Castaño¹Pablo Delgado-Wicke¹Nelly Daniela Zurita-Cruz²Nuria Montes^3,4Emilia Roy-Vallejo⁵Sara Fernández de Córdoba-Oñate⁶Ana Nicolao-Gómez¹Rosa Carracedo-Rodríguez¹Ana Marcos Jiménez⁷Laura Cardeñoso-Domingo²Isidoro González-Álvaro^8*Elena Fernández-Ruiz^1,9*

• ¹Molecular Biology Unit, Hospital Universitario de la Princesa, Madrid, Spain
• ²Microbiology Department, Hospital Universitario de la Princesa, Madrid, Spain
• ³Methodology Department, Hospital Universitario de la Princesa, Madrid, Spain
• ⁴Pharmaceutical and Health Sciences Department, Faculty of Pharmacy, Universidad CEU San Pablo, Madrid, Spain
• ⁵Internal Medicine Department, Hospital Universitario de la Princesa, Madrid, Spain
• ⁶Hematology Department, Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid, Spain
• ⁷Immunology Department, Hospital Universitario de la Princesa, Madrid, Spain
• ⁸Rheumatology Department, Hospital Universitario de la Princesa, Madrid, Spain
• ⁹Medicine Department, Universidad Autonoma de Madrid, Madrid, Spain

Background. The host response to SARS-CoV-2 depends on multiple factors including age, gender, underlying diseases and genetic background. Viral sensing and activation of the interferon signaling pathway in the early antiviral response could affect disease outcome. This study evaluated gene expression of Toll-like receptor 7 (TLR7), tyrosine kinase 2 (TYK2) and 2'-5' oligoadenylate synthetase 1 (OAS1) in two early longitudinal samples from mild, moderate and severe cases. Methods. Demographic and clinical variables were obtained from 157 COVID-19 patients. Peripheral blood mononuclear cells were used for genotyping and gene expression determination, and plasma for viremia detection, by qPCR and digital PCR, respectively. Gene expression was analyzed using Generalized Linear Mixed Models nested by patient. First, univariate analyses determined which variables were significantly associated with gene expression. Next, multivariate models were built with these variables, following the backward method. Results. TLR7 levels were higher in patients with mild disease compared to those with moderate disease and decreased over time. In contrast, patients with severe disease had lower TLR7 expression, which remained stable. OAS1 behavior was similar, whereas TYK2 remained unchanged. Multivariate analysis confirmed the relation of low TLR7 expression with severity and viremia. OAS1 levels directly correlated with higher viremia. TYK2 was associated with OAS1 expression, and OAS1 with both TLR7 and TYK2 levels. Conclusions. Low TLR7 levels were associated with severe COVID-19, and together with OAS1 expression were modulated over time according to severity. While TLR7 expression decreased across all severity groups as the disease resolved, OAS1 expression persisted in severe cases with higher viremia.