Table 3.

List of potential PCC animal models

Model	Similarities to human disease	Differences with the human disease	Neurological manifestations and laboratory findings	Technical considerations	References
GSH	• Naturally susceptible to SARS-CoV-2 infection • Multi-organ damage • No evidence of neuroinvasion • Spontaneous viral clearance	• Rapid humoral neutralizing immune response • Severe disease manifestations are limited by quick spontaneous viral clearance	• Accumulation of hyper -phosphorylated tau and α-synuclein in cortical neurons • Transcriptomic perturbations in the CNS • Behavioral changes	• Easy handling in the laboratory • Lack of hamster-specific research tools for the study of immune activation	21,52–55,72,86
Wild-type laboratory mice	• Susceptible to the Alpha, Beta, and Omicron SARS-CoV-2 variants with mild disease course	• Not susceptible to SARS-CoV-2 ancestral strain infection	• Neuroinflammation (observed with SARS-CoV-2 mouse adapted strain; studies limited to the acute phase)	• Easy handling in the laboratory • Wide availability of research tools	21,64,84–86
K18-hACE2-tg mice	• Susceptible to SARS-CoV-2 infection (multiple variants tested)	• Massive neuroinvasion and neuroinflammation • Lethal infection without viral clearance by 7 dpi	• Nonsuppurative meningoencephalitis • Diffuse astrogliosis and microgliosis • Apathy, depression, trembling and seizures	• Easy handling in the laboratory • Wide availability of research tools	21,43,73,74,76,78
hACE2-KI mice	• Susceptible to SARS-CoV-2 infection	• Minimal lung pathology	• Low amounts of viral RNA occasionally detected in brain samples • Studies limited to the acute phase	• Easy handling in the laboratory • Wide availability of research tools	78,94
AAV-hACE2 transduced mice (multiple strains)	• Mild to moderate respiratory disease • No neuroinvasion	• Targeted expression of hACE2 determines which organs and tissues are infected by SARS-CoV-2 • Transient hACE2 expression, dependent on the turnover rate of the transduced cells	• Increased CSF levels of CCL11 • Increased microglial activation in the subcortical white matter • Decreased neurogenesis in the hippocampus • Myelin loss	• Variability in results might depend on the AAV batch. • If used in different mouse strains (such as different humanized mice), the model allows for the study of specific pathways or immune cell types	59,61
NHPs	• Naturally susceptible to SARS-CoV-2 infection • Neuroinflammation observed without evidence of neuroinvasion • Spontaneous viral clearance	• Different NHP species display a heterogeneous spectrum of COVID-19 symptoms	• Neuroinflammation • Brain hypoxia • Neuronal morphological changes in cerebellum and brainstem	• Ethical limitations • Handling in the laboratory may be difficult depending on the species of choice	68,69,80

AAV, adeno-associated virus.