The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.

Safety and immunogenicity of an experimental live combination vaccine against enterovirus 71 and coxsackievirus A16 in rhesus monkeys.

Enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the two most common pathogens causing hand, foot, and mouth disease (HFMD). Previously, we obtained one candidate live attenuated strain each for EV-A71 and CV-A16; here, we evaluated the safety and immunogenicity of a combinedlive vaccine against EV-A71 and CV-A16 generated from these two candidate strains. Rhesus monkeys were intramuscularly treated with a live combinationvaccine against both EV-A71 and CV-A16 or with either vaccine alone. No fever or atypical clinical signs were observed in any animals. Monkeys vaccinated with the combinationlive vaccine presented no notable pathological changes in the brain, spinal cord, lung, and liver; in contrast, these regions showed inflammatory cell infiltration in monkeys treated with EV-A71 alone or CV-A16 alone. Weak viremia was detected in plasma after inoculation with the combinationvaccine; however, the duration of viral shedding in feces was increased. Biochemical studies revealed a slight increase in aspartate aminotransferase levels in monkeys inoculated with the live combination vaccine; however, histopathological findings did not attribute this change to liver damage. We also found that the live combinationvaccine induced a dual humoral immune response. Cytokine analysis indicated that the combined EV-A71/CV-A16 vaccine significantly down-regulated interleukin-8 production. Here, we have demonstrated that the live attenuated EV-A71/CV-A16 vaccine was safe and could trigger a dual specific immune response. However, its immune protection efficacy requires further investigation.

Monitoring and evaluation of the immune status of female Kunming mice maintained in different biosafety level laboratories.

High-level biosafety laboratories (BSL), such as BSL-3 and BSL-4, which deal with high infectivity and virulence pathogens, have become indispensable. Mice are frequently used in animal BSL (ABSL) to establish animal models for infection and to evaluate in vivo immune responses. A project of monitoring and evaluation on the physiology and immune status of mice housed in different ABSL labs was performed in the ABSL-2/3/4 labs of Kunming National High-level Biosafety Research Center, China. Female Kunming mice were housed in the ABSL-2/3/4 labs for 1 month, and mouse behavior, body physiology/immune status, pulmonary immune status and respiratory bacteria composition were evaluated and compared among mice from the different labs. Mice settled in their new housing environment of the different labs after transfer and gained weight steadily. Blood hematology testing, serum cytokine/chemokine profiles and blood/spleen lymphocyte constitutions were comparable between the ABSL-2/3/4 labs. The numbers of different pulmonary leukocytes in the bronchoalveolar lavage fluid were at baseline levels in mice from the ABSL-2/3/4 labs. Diversity and dominance of mice respiratory bacteria were semblable among the ABSL-2/3/4 labs. Our results confirm the stability of physiology and immune status of Kunming mice maintained in different ABSL-2/3/4 labs for at least 1 month.