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

TORO, AYELEN; LAGE-VICKERS, SOFIA; BIZZOTTO, JUAN; VILICICH, FELIPE; SABATER, AGUSTINA; PASCUAL, GASTON; LEDESMA-BAZAN, SABRINA; SANCHIS, PABLO; RUIZ, MARIA SOL; AREVALO, ANA PAULA; PORFIDO, JORGE L.; ABBATE, MERCEDES; SENIUK, ROCIO; LABANCA, ESTEFANIA; ANSELMINO, NICOLAS; NAVONE, NORA M.; ALONSO, DANIEL F.; VAZQUEZ, ELBA; CRISPO, MARTINA; COTIGNOLA, JAVIER; GUERON, GERALDINE

Viruses

MDPI

Año: 2022 vol. 14

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 MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient’s viral load. Expression of MX1, MX2, ISG15, and OAS1 (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 STAT1/JAK2 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.