Researchers in the United States have validated a feline model of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that closely imitates coronavirus disease 2019 (COVID-19) in humans.
The team – from Oklahoma State University in Oklahoma and Tulane University in Los Angeles – says that the challenges with previous feline models have been a lack of clinical disease of the lower respiratory tract that resembles the lesions seen in COVID-19 patients.
The researchers used a novel clinical scoring system for feline respiratory disease that revealed a significant degree of lethargy, fever, dyspnea, and dry cough in infected cats.
Pulmonary lesions were also observed that resembled those seen in COVID-19 patients hospitalized with acute respiratory distress syndrome (ARDS).
“The applicability of a clinically significant SARS-CoV-2 feline model with pathological lesions that mirror severe COVID-19 is of high impact for future studies,” writes Craig Miller and colleagues.
A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.
Efficient animal models are urgently needed
The emergence of COVID-19 and novel SARS-CoV-2 variants that threaten to increase the duration of the pandemic highlight the urgent need for efficient animal models of infection to improve understanding of host immune responses and inform the development of therapeutics.
Mortality resulting from COVID-19 is closely correlated with progression to severe lung disease (pneumonia) and respiratory failure due to ARDS.
However, the hallmark pulmonary features of severe COVID-19, such as diffuse alveolar damage, hyaline membrane formation, type II pneumocyte hyperplasia, and vascular thrombi, have been difficult to reproduce in animal models.
Miller and colleagues say this has made it impossible to thoroughly understand the pathophysiology of disease and test the efficacy of new therapeutics and vaccines.
Where do cats come in?
Cats have previously been successfully inoculated with SARS-CoV-2 via intra-nasal and intra-oral routes but have failed to produce clinical signs of infection and lower respiratory pathology that resembles severe COVID-19 in humans, potentially due to the concentration of the viral inoculum or the inoculation route.
Interestingly, pulmonary disease with diffuse alveolar damage was previously observed in a study of cats that were intratracheally infected with 1x106 TCID50 SARS-CoV-1, says Miller and colleagues.
“Based on outcomes of these former studies, we hypothesized that inoculation with a higher concentration of SARS-CoV-2 via the intra-tracheal route would result in pulmonary pathology and clinical disease in domestic cats similar to COVID-19 in human patients,” they write.
Intra-tracheal inoculation at a higher dose
The team inoculated twelve cats with SARS-CoV-2 via the intra-tracheal route and at a higher concentration (1.26x106 TCID50)than previously reported.
To carefully assess for clinical disease, the researchers designed a novel clinical scoring system for feline respiratory disease.
The results revealed signs of clinical disease in the animals that were similar to those described for patients hospitalized with COVID-19.
Clinical disease in hospitalized patients is characterized by fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), and fatigue (38%).
Among the SARS-CoV-2-infected cats studied here, predominant clinical signs included fever, cough, lethargy and increased respiratory effort.
The cats also exhibited pulmonary lesions such as diffuse alveolar damage and evidence of vascular damage.
The specific histopathological lesions observed aligned closely with those reported in COVID-19 patients, including diffuse alveolar damage with hyaline membrane formation, type II pneumocyte hyperplasia, fibrinous exudate and vascular thrombi.
“To the author’s knowledge, this is the first report of hyaline membrane formation and type II pneumocyte hyperplasia in feline SARS-CoV-2 infection, which are classic characteristics of human SARS-CoV-2 infection,” says Miller and the team.
Fluorescent immunohistochemistry for SARS-207 CoV-2 nucleoprotein identifies mononuclear cells in tracheobronchial lymph node of intratracheally-infected cats. Low numbers of SARS-CoV-2 positive cells (green, white arrows) are detected in (A) positive control tissue (lung) from an African Green Monkey infected with SARS-CoV-2 , and within (B) mononuclear cells in the TB LN of SARS-CoV-2 infected cats (green, white arrow). White = DAPI/nuclei; green = CoV-2. Magnification (A-B) 40x, scale bar = 20 μm.
What are the study implications?
The researchers say the study provides the first feline model of SARS-CoV-2 infection with significant lower respiratory disease that displays features of the diffuse alveolar damage seen in the early exudative phase of human COVID-19.
The differences in clinical presentation between previous feline models and the one described here are likely due to the difference in the inoculation route and dose, they add.
The team says the model could be used in future studies to investigate novel therapeutics for COVID-19.
“Therapeutic measures can be thoroughly assessed for improvement in pathology and mitigation of clinical disease in cats before being validated in human trials, and more thorough evaluation of the feline immune response to infection may elucidate other options for COVID-19 treatments that could mitigate disease and improve clinical outcomes,” writes Miller and colleagues.
“This animal model offers an ease of use, which may positively impact further vaccination and control strategies necessary to achieve an end to the rapid spread of COVID-19,” they conclude.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.