Abstract
Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats ( n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein-cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.
Keywords: B.1.617.2; Delta variant; SARS-CoV-2; disease transmission; domestic cats; feline; inflammatory pathways; pathology.
【저자키워드】 SARS-CoV-2, pathology, B.1.617.2, delta variant, feline, domestic cats, disease transmission, inflammatory pathways, 【초록키워드】 SARS CoV-2, pathology, SARS-COV-2 infection, hub genes, variant, SARS-CoV-2 variant, Infection, Delta, B.1.617.2, lung, nasal, animal model, animal models, progression, immunopathology, delta variant, virus, pulmonary inflammation, chemokine, COVID-19 disease, Spread, Disease progression, SARS-CoV-2 variants, non-human primates, acute infection, Lungs, RNA sequencing, Respiratory disease, therapeutic, pathway, Cluster, Mild, network analysis, Vasculitis, target, correlation, disease, Critical, Differentially expressed genes, interactions, WGCNA, differentially expressed gene, disease transmission, Pneumocytes, Interaction, Infectious virus, dose, Inflammatory, inflammatory pathways, lesion, Post-infection, Viral antigen, Vascular endothelium, Viral protein, Divergence, SARS CoV, lesions, secretion, help, transgenic mice, lung tissue, pulmonary lesions, wild-type SARS-CoV-2, upregulation, limitation, ferrets, circulating, acute COVID-19, timepoints, cytokine receptor, ACE2-expressing cells, downstream, Clinical sign, Host, chemokine signaling, Prevent, genetic modification, highlight, COVID-19 disease course, flexible, identify, develop, evaluate, significantly, include, intranasally, inoculated, correlated, dysregulated, pulmonary lesion, translational, ACE2-expressing cell, peribronchial, 【제목키워드】 Delta, Kinetics,