Overexpression of OAS Genes in Severe COVID-19: A Cross-Sectional Study of Hospitalized Patients Infected with Delta and Omicron Variants

<b>Background/Objectives</b>: COVID-19 is an infectious disease caused by SARS-CoV-2. The innate immune response constitutes the first line of antiviral defense. Notably, interferon-stimulated genes, such as those belonging to the oligoadenylate synthetase (<i>OAS</i>) family, have been implicated in host susceptibility and the response to SARS-CoV-2 infection. However, the extent to which <i>OAS</i> gene expression varies across SARS-CoV-2 variants remains insufficiently characterized. Its relationship with clinical outcomes in hospitalized patients is also unclear. This study aimed to evaluate <i>OAS</i> gene expression and its association with inflammatory markers and clinical outcomes in patients with severe COVID-19. <b>Methods</b>: An analytical cross-sectional study was conducted in patients hospitalized with severe COVID-19 between October 2021 and February 2022. SARS-CoV-2 infection and viral variants were prescreened at admission. Clinical parameters were recorded, including serum cytokine levels (IL-1β, IL-6, IL-8, MCP-1, IFN-α, IFN-β, IFN-γ, and TNF-α), and hematological indices (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio). The COVID-GRAM risk score, treatment, and hospitalization outcomes were recorded. Relative mRNA expression of <i>OAS1</i>, <i>OAS2</i>, <i>OAS3</i>, and <i>OAS-L</i> was quantified by quantitative PCR, using <i>TaqMan</i> probes. <b>Results</b>: A total of 76 hospitalized patients with severe COVID-19 were included. In-hospital mortality was 32.9%, with a predominance of male patients (60%). Nearly 50% of non-survivors were infected with the Omicron variant. <i>OAS1</i>, <i>OAS2</i>, and <i>OAS3</i> were overexpressed in hospitalized patients with severe COVID-19 compared with healthy subjects (HS) (log₂ fold change [95% CI]: <i>OAS2</i>: 4.312 [4.161-4.602], <i>OAS3</i>: 1.660 [1.485-1.916]; <i>p</i> = 0.0040 for both). Expression of <i>OAS2</i> and <i>OAS3</i> was significantly increased in survivors compared with HS (log₂ fold change: 4.312 [4.161-4.602] and 1.711 [1.485-1.990], respectively; <i>p</i> = 0.0009 and <i>p</i> = 0.0025). Similar increases were observed in non-survivors (4.554 [4.251-4.743] and 1.640 [1.081-2.301], respectively; <i>p</i> = 0.0002 and <i>p</i> = 0.0061) compared with HS. <b>Conclusions</b>: <i>OAS</i> genes, particularly <i>OAS2</i> and <i>OAS3</i>, are overexpressed in severe COVID-19. This upregulation was comparable between Delta and Omicron infections, suggesting that the activation of this antiviral pathway is driven more by disease severity than by the specific viral variant.