The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation
Abstract Evidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 ± 0.024 μL/g-min and 0.294 ± 0.032 μL/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10ththe amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis.Graphical Abstract <jats:fig id="ufig1" position="anchor" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="205229v1_ufig1" position="float" orientation="portrait" /></jats:fig>.
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 04. Okt. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rhea, Elizabeth M. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.07.15.205229 |
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| PPN (Katalog-ID): |
XBI018364349 |
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| 245 | 1 | 0 | |a The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation |
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| 520 | |a Abstract Evidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 ± 0.024 μL/g-min and 0.294 ± 0.032 μL/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10ththe amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis.Graphical Abstract <jats:fig id="ufig1" position="anchor" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="205229v1_ufig1" position="float" orientation="portrait" /></jats:fig> | ||
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| 700 | 1 | |a Logsdon, Aric F. |4 aut | |
| 700 | 1 | |a Hansen, Kim M. |4 aut | |
| 700 | 1 | |a Williams, Lindsey |4 aut | |
| 700 | 1 | |a Reed, May |4 aut | |
| 700 | 1 | |a Baumann, Kristen |4 aut | |
| 700 | 1 | |a Holden, Sarah |4 aut | |
| 700 | 1 | |a Raber, Jacob |4 aut | |
| 700 | 1 | |a Banks, William A. |0 (orcid)0000-0002-0496-3619 |4 aut | |
| 700 | 1 | |a Erickson, Michelle A. |4 aut | |
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