- Lack of natural COVID-19 infectivity- Insufficient affinity of murine ACE2 and SARS-CoV-2 S protein- Need of transgenic expression of hACE2 or viral adaptation is required- Non physiological conditions of the SARS-CoV-2 infection- CNS affected by neuro-invasion, lethal encephalitis- hACE2 tissue distribution and expression levels in knock-in mice- Differences in susceptibility for SARS-CoV-2 based on gender and age- Study of mild to moderate COVID-19, not severe illness- Limited availability- Relatively long breeding time. Here, ACE2 is linked to encephalitis.