key: cord-0966978-i2pjsc3a
authors: Qin, Shengle; Li, Runfeng; Zheng, Zhaoguang; Zeng, Xuxin; Wang, Yutao; Wang, Xinhua
title: Review of selected animal models for respiratory coronavirus infection and its application in drug research
date: 2022-03-24
journal: J Med Virol
DOI: 10.1002/jmv.27718
sha: 2401860e27311293266efcf08dcbb9bec0f530d9
doc_id: 966978
cord_uid: i2pjsc3a

Numerous viral pneumonia cases have been reported in Wuhan, Hubei in December 2019. The pathogen has been identified as a novel coronavirus, which was named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The biological characteristics and pathogenesis mechanism of SARS‐CoV‐2 are unclear and under progress. At present, no specific preventive and therapeutic drugs are available. Animal models can reproduce the viral replication cycle and the significant functions of respiratory coronavirus infection and are urgently needed to evaluate the efficacy of drugs and vaccines, the transmission route of respiratory coronavirus, clinical features, and so on. We reviewed the current animal models of respiratory coronavirus (SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2) infection and made a comparative analysis of the route of inoculation, virus replication, clinical signs, histopathology, application, advantages, and disadvantages. Animal models of respiratory coronavirus include susceptible animal models, genetically modified models, and various animal models of infected virus adaptation strains, such as nonhuman primates, mice, hamsters, ferrets, New Zealand rabbits, cats, and other animal models, all of which have distinct advantages and limitations. This review will provide relevant information and important insights for disease management and control.

caused human respiratory diseases. Coronaviruses are enveloped viruses containing single-stranded RNA and can be divided into α, β, γ, and δ genera, among which α and β coronaviruses are related to human diseases. HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU-1 coronavirus can cause mild respiratory disease and even pneumonia and lower respiratory tract diseases in immunocompromised individuals. 3 The antiviral activity against SARS-CoV-2 was evaluated in mice, 5 ferret, 6 hamsters, 7 and rhesus macaques model. 8 Molnupiravir (EIDD-2801, MK-4482) is an orally bioavailable NHC-prodrug (β-D-N 4hydroxycytidine-5′-isopropyl ester), which is effective against SARS-CoV-2 infections in Syrian hamsters, 9 mice, 10 and ferrets. 11 Current animal models for respiratory coronavirus infection include nonhuman primates, mice, hamsters, ferrets, New Zealand rabbits, cats, and so on. We reviewed the animal models of respiratory coronavirus SARS-CoV (Table 1) , MERS-CoV (Table 2) , and SARS-CoV-2 (Table 3) infection and made a comparative analysis from the route of inoculation, virus replication, clinical signs, histopathology, application, advantages, and disadvantages.

Nonhuman primates, such as macaca mulatta, cynomolgus macaques, the common marmosets, African green monkeys, are generally susceptible to human respiratory coronavirus regarded as ideal experimental models.

Among them, Macaca mulattas are the most widely used.

Macaca mulattas were sensitive to SARS-CoV, SARS-CoV-2, and MERS-CoV, and the infection response was apparent. 34 In Macaca mulatta, fever develops 2-3 days after nasal inoculation with SARS-CoV. Within 5-60 days, pathological changes in the lungs, including hemorrhage, edema and diffuse lesions, septal macrophages, and lymphocyte infiltration, are continuously observed. SARS-CoV virus can be detected in the throat and nasal swab samples within 1-16 days after infection. 12 Macaca mulatta infected with SARS-CoV-2 developed respiratory diseases lasting from 8 to 16 days, including cough, weight loss, loss of appetite, pallor, and dehydration, as well as changes in respiratory patterns. Pathological changes included mild to moderate interstitial pneumonia and X-rays of the lungs revealing infiltrates.

SARS-CoV-2 replicates in the respiratory tract, and high viral load can be detected in bronchoalveolar lavage. Additionally, the virus can also be recovered from lymph and gastrointestinal tissues and shed for up to 27 days via the nose and feces. 22 dyspnea. An autopsy showed significant interstitial lung disease, including edema, bronchiolar congestion, interstitial infiltration, and a very high viral load in the lungs. 17 In African green monkeys infected with MERS-CoV by aerosol, pulmonary disease symptoms increased in a dose-dependent manner.

After infection, they presented clinical manifestations of dehydration, wheezing, and lung rales. The pathological changes were multifocal interstitial pneumonia, and the virus can be detected in the nose swab serum. 18 Importantly, African green monkeys also support the replication of SARS-CoV-2 in vivo and exhibit severe respiratory disease. African green monkeys infected with SARS-COV-2 showed decreased appetite, increased body temperature, and higher partial pressure of oxygen dioxide. Significant inflammation and clotting were found in the tissue and blood, and autopsies also showed pulmonary congestion and histological differing degrees of multifocal lung disease. Simultaneously, high viral load can be detected in nasal and rectal swabs. 24 

The receptor-binding domain of the spike protein is important for the entry of the virus into the cell. The spike protein is split into S1 and S2 by protease after entering the host cell, and S1 binds to the receptor of the host cell, allowing the virus to enter the cell. However, MERS-CoV cannot replicate in Golden hamsters, possibly due to virus replication being limited at cellular levels. 42 In addition, Roborovski Dwarf Hamster is also highly prone to SARS-CoV-2.

On Day 1 post infection, clinical symptoms, such as hypothermia, reduced activity, and breathing difficulties, were observed, which was consistent with pathological findings of severe acute diffuse vesicle damage, and hyaluronic acid microthrombosis. 32

The ferrets infected with SARS-CoV showed elevated body temperature, runny nose, sneezing, and other clinical manifestations, and pathological changes in interstitial pneumonia, pus pneumonia, and pulmonary edema were observed in the upper respiratory tract. 15 Ferrets can be infected with SARS-CoV-2 through direct and indirect contact. 43 After infection with SARS-CoV-2, the temperature of the ferret rises. Viruses replicate in the host body and can be detected in the blood, nasal armor, trachea, lungs, and intestines. 

The rhesus macaque was used to evaluate the efficacy of remdesivir The total dose of 2.6 × 10 6 TCID 50 SARS-CoV-2 was administered intranasally, orally, intraophthalmally, and intravenously.

Remdesivir was given intravenously at 10 mg/kg at 12 h after infection and intravenously at 5 mg/kg every 24 h thereafter.

The results confirmed that early treatment with remdesivir reduced lung viral load and lung injury in rhesus monkeys. 8 Ferrets were used to evaluate the efficacy of oral antiviral drugs.

Ferrets were inoculated intranasally with 1 × 10 5 pfu SARS-CoV-2.

After infection, remdesivir was given orally at 10 mg/kg twice daily investigation. An ideal animal model is an important tool for studying viral diseases, which cannot be confirmed in vitro culture experiments, and the top concern for animal models is to imitate well the key features observed under clinical conditions. But the limitation is that the hamster model is not fatal and lacks generally available reagents.

Ferrets are a very important and useful model for the study of respiratory viruses in general, such as influenza viruses, SARS-CoV. 54 Ferret model also can be infected through direct and indirect ways and is a better model for evaluation of SARS-CoV-2 transmission. but it is only mild clinical symptoms and relatively lower virus titers in the lungs of an infected animal, and also, ferret-specific immunological reagents are scarcer.

These small animal models are smaller in size and small space required, they are easier to get and have better operability and repeatability, especially the mice which are easier to control, cheaper, and large numbers for data analysis.

Nonhuman primates belong to large animal models. These 

The authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data are available from the corresponding author upon reasonable request.

The peer review history for this article is available at https://publons. com/publon/10.1002/jmv.27718

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