Despite the growing list of identified SARS-CoV-2 receptors, the human angiotensin-converting enzyme 2 (ACE2) is still viewed as the main cell entry receptor mediating SARS-CoV-2 internalization. It has been reported that wild-type mice, like other rodent species of the Muridae family, cannot be infected with SARS-CoV-2 due to differences in their ACE2 receptors. On the other hand, the consensus heparin-binding motif of SARS-CoV-2's spike protein, PRRAR, enables the attachment to rodent heparan sulfate proteoglycans (HSPGs), including syndecans, a transmembrane HSPG family with a well-established role in clathrin- and caveolin-independent endocytosis. As mammalian syndecans possess a relatively conserved structure, we analyzed the cellular uptake of inactivated SARS-CoV-2 particles in in vitro and in vivo mice models. Cellular studies revealed efficient uptake into murine cell lines with established syndecan-4 expression. After intravenous administration, inactivated SARS-CoV-2 was taken up by several organs in vivo and could also be detected in the brain. Internalized by various tissues, inactivated SARS-CoV-2 raised tissue TNF-α levels, especially in the heart, reflecting the onset of inflammation. Our studies on in vitro and in vivo mice models thus shed light on unknown details of SARS-CoV-2 internalization and help broaden the understanding of the molecular interactions of SARS-CoV-2.

Boeckeler Instruments Inc Tucson AZ 85714 USA

Delong Instruments a s 612 00 Brno Czech Republic

Department of Medicine Albert Szent Györgyi Clinical Center Faculty of Medicine University of Szeged H 6720 Szeged Hungary

Institute of Biochemistry Biological Research Centre H 6726 Szeged Hungary

Institute of Biophysics Biological Research Centre H 6726 Szeged Hungary

Laboratory of Proteomics Research Biological Research Centre H 6726 Szeged Hungary

Pharmacoidea Ltd H 6726 Szeged Hungary

Theoretical Medicine Doctoral School Faculty of Medicine University of Szeged H 6720 Szeged Hungary

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