Look what the cat dragged in! Infection kinetics of SARS-CoV-2 variants in the feline model of COVID-19

Abstract

The continued dominance of COVID-19 worldwide underscores the critical need for efficient animal models to develop therapeutics and assess immune responses to SARS-CoV-2 infection. Previous studies by our lab have established a feline model of natural SARS-CoV-2 infection that results in clinical disease and histopathologic lesions consistent with acute COVID-19 in humans. In these initial studies, domestic cats (n=18) were intratracheally inoculated with wild-type SARS-CoV-2 (WA isolate) and exhibited significant clinical disease (lethargy, fever, dyspnea, dry cough) consistent with the early exudative phase of COVID-19. Pulmonary lesions (diffuse alveolar damage, hyaline membrane formation, fibrin deposition, proteinaceous exudates) were also observed with wild-type SARS-CoV-2 infection, replicating lesions in people hospitalized with COVID-19-induced ARDS. Recent analysis of this data has also documented significant shifts in lymphocyte immunophenotypes of cats infected with wild-type SARS-CoV-2, as well as increased expression of systemic pro-inflammatory cytokines and upregulation of pro-inflammatory pathways (p38 MAPK, NF-kB) in lung tissues associated with severe pulmonary disease. In a separate study, we show that intratracheal inoculation with the delta variant of SARS-CoV-2 (B.1.617.2) produces severe clinical respiratory disease and pulmonary lesions in domestic cats (n=24), even at 1/10 the dose of wild-type SARS-CoV-2. Infectious virus was isolated form nasal secretions of delta-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 is more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing analysis of lung samples from infected cats identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, apoptosis, and viral protein-cytokine interactions during acute infection with SARS-CoV-2, along with several other inflammatory pathways such as NF-kB and JAK-STAT signaling. Collectively, the results of these studies help delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop control strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.

Biography

Bio: Craig Miller, DVM, PhD, Diplomate ACVP, is a veterinary anatomic pathologist and Director of the Immunopathology Core Laboratory in the Oklahoma Center for Respiratory and Infectious Diseases (OCRID) at Oklahoma State University.  He also serves as a diagnostic pathologist at the Oklahoma Animal Disease Diagnostic Laboratory (OADDL). Dr. Miller earned his BS, DVM, and PhD degrees from Colorado State University, completed a residency in Veterinary Anatomic Pathology at the Colorado State Veterinary Diagnostic Laboratory (CSU-VDL), and is a Diplomate of the American College of Veterinary Pathologists since 2017.

Dr. Miller's research endeavors are focused primarily on understanding the immunopathology of infectious diseases, and has established the Companion Animal and Translational Science laboratory (C.A.T.S. Lab) at Oklahoma State University which uses translational feline models to investigate solutions to human disease.  The C.A.T.S. Lab is focused on understanding the complex interactions that develop between pathogens and host immune dysfunction, and employs a wide array of immunologic assays (flow cytometry, microsphere immunoassay, immunohistochemistry) and cutting edge molecular techniques (droplet digital PCR, single cell RNA sequencing) to characterize innate and cell-mediated immune dyscrasias associated with viral (SARS-CoV-2, HIV/FIV) and protozoal (Cytauxzoon felis) infections. Current work is actively focused on development and application of feline models for SARS-CoV-2 infection to study immune dysfunction contributing to COVID-19 progression, as well as the development of novel diagnostics, therapeutics, and vaccination strategies to prevent cytauxzoonosis (i.e. Bobcat Fever). Dr. Miller is a member of the American Veterinary Medical Association, Phi Zeta Honor Society, and the American College of Veterinary Pathologists.