Investigating the Effect of Enterally Administered Capromorelin on Body Weight in Mice (Mus musculus).

Significant weight loss in mice (Mus musculus) is a welfare concern and can alter physiology and behavior in ways that may confound research aims. In this study, factorial design was used to investigate the effect of enterally administered capromorelin on changes in mouse body weight overall and with various research-related interventions, such as administration of analgesics, anesthesia, or surgery. BALB/c mice (n = 61 [27 males/34 females] for analysis) were randomized into 8 intervention-treatment groups with 2 treatment allocations: capromorelin (10 mg/kg) or control, and 4 intervention allocations: no intervention; buprenorphine extended-release (XR) alone; buprenorphine XR, meloxicam, and anesthesia; or surgery under anesthesia with buprenorphine XR, meloxicam, and bupivacaine administered. Mice were habituated to handling, weighing, and voluntary consumption of condensed milk, which was used as the control solution and later a vehicle for capromorelin delivery, for 5 d (days 0 to 4). Then, mice received their interventions followed by 3 days of daily treatment or control administration (days 7 to 9). Body weights were measured daily (days 8 to 11 and day 14) to compare with baseline weights (days 0 to 4 and day 7) and evaluate for treatment and intervention effects on body weight. The interventions resulted in a decrease in group body weights 3 and 4 d after the interventions were conducted. Overall, body weights increased more in mice given capromorelin compared with control, and mice treated with capromorelin returned to, or exceeded, baseline weights faster. The weight loss was mitigated by capromorelin administration in all interventions except for the buprenorphine XR-only group. It is recommended to clinically consider enterally administered capromorelin to mitigate research-induced weight loss in mice.

Hamsters Expressing Human Angiotensin-Converting Enzyme 2 Develop Severe Disease following Exposure to SARS-CoV-2.

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global health emergency. While most human disease is mild to moderate, some infections lead to a severe disease characterized by acute respiratory distress, hypoxia, anosmia, ageusia, and, in some instances, neurological involvement. Small-animal models reproducing severe disease, including neurological sequela, are needed to characterize the pathophysiological mechanism(s) of disease and to identify medical countermeasures. Transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the K18 promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge when high viral doses are used. Here, we report on SARS-CoV-2 infection of hamsters engineered to express the hACE2 receptor under the control of the K18 promoter. K18-hACE2 hamsters infected with a relatively low dose of 100 or 1,000 PFU of SARS-CoV-2 developed a severe and lethal disease, with most animals succumbing by day 5 postinfection. Hamsters developed severe lesions and inflammation within the upper and lower respiratory system, including infection of the nasal cavities causing marked destruction of the olfactory epithelium as well as severe bronchopneumonia that extended deep into the alveoli. Additionally, SARS-CoV-2 infection spread to the central nervous system (CNS), including the brain stem and spinal cord. Wild-type (WT) hamsters naturally support SARS-CoV-2 infection, with the primary lesions present in the respiratory tract and nasal cavity. Overall, infection in the K18-hACE2 hamsters is more extensive than that in WT hamsters, with more CNS involvement and a lethal outcome. These findings demonstrate the K18-hACE2 hamster model will be valuable for studying SARS-CoV-2. IMPORTANCE The rapid emergence of SARS-CoV-2 has created a global health emergency. While most human SARS-CoV-2 disease is mild, some people develop severe, life-threatening disease. Small-animal models mimicking the severe aspects of human disease are needed to more clearly understand the pathophysiological processes driving this progression. Here, we studied SARS-CoV-2 infection in hamsters engineered to express the human angiotensin-converting enzyme 2 viral receptor under the control of the K18 promoter. SARS-CoV-2 produces a severe and lethal infection in transgenic hamsters that mirrors the most severe aspects of COVID-19 in humans, including respiratory and neurological injury. In contrast to other animal systems, hamsters manifest disease with levels of input virus more consistent with natural human infection. This system will be useful for the study of SARS-CoV-2 disease and the development of drugs targeting this virus.

Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure.

Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to determine critical disease parameters associated with disease progression, and establish correlations between primate and human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation.