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

Author:

Toro AyelenORCID,Lage-Vickers Sofia,Bizzotto Juan,Vilicich Felipe,Sabater AgustinaORCID,Pascual Gaston,Ledesma-Bazan SabrinaORCID,Sanchis Pablo,Ruiz Maria SolORCID,Arevalo Ana Paula,Porfido Jorge L.,Abbate Mercedes,Seniuk RocioORCID,Labanca Estefania,Anselmino Nicolas,Navone Nora M.ORCID,Alonso Daniel F.ORCID,Vazquez ElbaORCID,Crispo MartinaORCID,Cotignola JavierORCID,Gueron GeraldineORCID

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 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.

Funder

Agencia Nacional de Promocion de la Investigacion, el Desarrollo Tecnologico y la Innovación (ANPCyT), Argentina

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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