Pin-Pointing the Key Hubs in the IFN-γ Pathway Responding to SARS-CoV-2 Infection

Abstract

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of <i>MAP2K6</i>, <i>CBL</i>, <i>RUNX3</i>, <i>STAT1</i>, and <i>JAK2</i> in COVID-19-positive vs. -negative patients. A positive correlation was observed between <i>STAT1</i>/<i>JAK2</i>, which varied alongside the patient's viral load. Expression of <i>MX1</i>, <i>MX2</i>, <i>ISG15</i>, and <i>OAS1</i> (four well-known IFN-stimulated genes (ISGs)) displayed upregulation in COVID-19-positive vs. -negative patients. Integrative analyses showcased higher levels of ISGs, which were associated with increased viral load and <i>STAT1</i>/<i>JAK2</i> expression. Confirmation of ISGs up-regulation was performed in vitro using the A549 lung cell line treated with Poly (I:C), a synthetic analog of viral double-stranded RNA; and in different pulmonary human cell lines and ferret tracheal biopsies infected with SARS-CoV-2. A pre-clinical murine model of Coronavirus infection confirmed findings displaying increased ISGs in the liver and lungs from infected mice. Altogether, these results demonstrate the role of IFN-γ and ISGs in response to SARS-CoV-2 infection, highlighting alternative druggable targets that can boost the host response.