Characterization of a mouse model as a predictive tool for human Post‐Acute Sequelae of Covid‐19

Abstract

AbstractBackgroundWhile initial effects of Covid‐19 are concentrated in the respiratory system, numerous neurological symptoms and complications have been documented both during the acute disease course, as well as lingering symptoms following infection. Emerging reports have documented a multitude of transcriptional, proteomic, and homeostatic changes following acute infection. Here, we systematically evaluate a transgenic mouse model, a 5xFAD x hACE2, for its ability to recapitulate key underlying PASC‐pathologies.MethodFive month hACE2 x 5xFAD double transgenic mice were intranasally inoculated with SARS‐CoV‐2 and sacrificed seven days post infection. Murine brain samples from the parietotemporal cortex and hippocampus, and matched postmortem SARS‐CoV‐2 infected, AD, healthy control, and AD + SARS‐CoV‐2 infected brain samples were submitted for RNA‐sequencing. Congruency analyses with upset plots and immunohistochemistry were performed to evaluate the ability of the murine model to recapitulate human findings.Result5xFAD x hACE2 mice exhibited key overlapping transcriptional changes common to humans, including BBB dysfunction, impaired synaptogenesis, and leukocyte dysfunction. Glial activation and distribution of virus was also recapitulated in our mouse model. Through dimensionality reduction and the integration of multimodal data, this model exhibits a similar etiopathogenesis to our findings in human.ConclusionThese studies provide a strong evidentiary basis for the utilization of a 5xFAD x hACE2 mouse model for modelling human PASC. Additional future studies utilizing this model to elucidate mechanisms underlying neuropathogenesis and the investigation of novel therapeutics is warranted.