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

• DOI: 10.1371/journal.pone.0317921
• Publication Date: 2025-01-28T18:45:36Z
• Authors: Vivian Y. Tat; Aleksandra K. Dre...; Pinghan Huang; Kamil Khanipov; Jason C. Hsu; Steven G. Widen; Chien-Te Kent Tseng; George Golovko
• Keywords: Science; Q; R; Medicine; Research Article

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.