Journal Article

Characterizing temporal and global host innate immune responses against SARS-CoV-1 and -2 infection in pathologically relevant human lung epithelial cells

Khanipov, Kamil, Tat, Vivian Y., Golovko, George, Hsu, Jason C., Huang, Pinghan, Tseng, Chien-Te Kent, Drelich, Aleksandra K., Widen, Steven G.

2025

Overview

Severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and -2 (SARS-CoV-2) are beta-coronaviruses (β-CoVs) that have caused significant morbidity and mortality worldwide. Therefore, a better understanding of host responses to β-CoVs would provide insights into the pathogenesis of these viruses to identify potential targets for medical countermeasures. In this study, our objective is to use a systems biology approach to explore the magnitude and scope of innate immune responses triggered by SARS-CoV-1 and -2 infection over time in pathologically relevant human lung epithelial cells (Calu-3/2B4 cells). Total RNA extracted at 12, 24, and 48 hours after β-CoVs or mock infection of Calu-3/2B4 cells were subjected to RNA sequencing and functional enrichment analysis to select genes whose expressions were significantly modulated post-infection. The results demonstrate that SARS-CoV-1 and -2 stimulate similar yet distinct innate antiviral signaling pathways in pathologically relevant human lung epithelial cells. Furthermore, we found that many genes related to the viral life cycle, interferons, and interferon-stimulated genes (ISGs) were upregulated at multiple time points. Based on their profound modulation upon infection by SARS-CoV-1, SARS-CoV-2, and Omicron BA.1, four ISGs, i.e., bone marrow stromal cell antigen 2 ( BST2 ), Z-DNA Binding Protein 1 ( ZBP1 ), C-X-C Motif Chemokine Ligand 11 ( CXCL11 ), and Interferon Induced Transmembrane Protein 1 ( IFITM1 ), were identified as potential drug targets against β-CoVs. Our findings suggest that these genes affect both pathogens directly and indirectly through the innate immune response, making them potential targets for host-directed antivirals. Altogether, our results demonstrate that SARS-CoV-1 and SARS-CoV-2 infection induce differential effects on host innate immune responses.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Antiviral agents / Antiviral drugs / Biology and life sciences / Bone marrow / Cell Line / Chemokines / Coronaviruses / COVID-19 / COVID-19 - immunology / COVID-19 - virology / CXCL11 protein / DNA structure / Epithelial cells / Epithelial Cells - immunology / Epithelial Cells - virology / Epithelium / Gene expression / Gene sequencing / Gene set enrichment analysis / Generalized linear models / Genes / Humans / Immune response / Immune system / Immunity, Innate - genetics / Infections / Innate immunity / Interferon / Lung - immunology / Lung - pathology / Lung - virology / Lungs / Medicine and health sciences / Morbidity / Ontology / Pathogenesis / Pathogens / Pattern recognition receptors / Penicillin / Proteins / Respiratory diseases / Ribonucleic acid / RNA / RNA sequencing / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / Severe acute respiratory syndrome-related coronavirus - immunology / Signal Transduction / Software / Therapeutic targets / Thermal cycling / Viral diseases / Viral infections / Z-form