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

Authors

Ayelen Toro
Sofia Lage-Vickers
Juan Bizzotto
Felipe Vilicich
Agustina Sabater
Gaston Pascual
Sabrina Ledesma-Bazan
Pablo Sanchis
Maria Sol Ruiz
Ana Paula Arevalo
Jorge L Porfido
Mercedes Abbate
Rocio Seniuk
Estefania Labanca
Nicolas Anselmino
Nora M Navone
Daniel F Alonso
Elba Vazquez
Martina Crispo
Javier Cotignola
Geraldine Gueron

Publication Date

9-30-2022

Journal

Viruses

DOI

10.3390/v14102180

PMID

36298734

PMCID

PMC9610092

PubMedCentral® Posted Date

9-30-2022

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Animals, Mice, COVID-19, Interferon-gamma, SARS-CoV-2, Case-Control Studies, RNA, Double-Stranded, Ferrets, MAP Kinase Kinase 6, IFN-γ, ISGs

Published Open-Access

yes

Recommended Citation

Toro, Ayelen; Lage-Vickers, Sofia; Bizzotto, Juan; et al., "Pin-Pointing the Key Hubs in the IFN-γ Pathway Responding to SARS-CoV-2 Infection" (2022). Faculty, Staff and Student Publications. 4667.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4667