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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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 1/10 th the 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.
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SciScore for 10.1101/2020.07.15.205229: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Mice: All mouse studies were approved by the local IACUC at OHSU and the VA Puget Sound Healthcare System and conducted in AAALAC approved facilities. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Male CD-1 mice (6-10 weeks old) were purchased from Charles River Laboratories (Hollister, Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Effects of Inflammation: Treatment with Lipopolysaccharide: Male CD-1 mice aged 6-10 weeks were given an ip injection of 3 mg/kg LPS from Salmonella typhimurium (Sigma, St. Louis, MO) dissolved in sterile normal saline at 0, 6, and 24 h. CD-1suggest…SciScore for 10.1101/2020.07.15.205229: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: Mice: All mouse studies were approved by the local IACUC at OHSU and the VA Puget Sound Healthcare System and conducted in AAALAC approved facilities. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable Male CD-1 mice (6-10 weeks old) were purchased from Charles River Laboratories (Hollister, Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources Effects of Inflammation: Treatment with Lipopolysaccharide: Male CD-1 mice aged 6-10 weeks were given an ip injection of 3 mg/kg LPS from Salmonella typhimurium (Sigma, St. Louis, MO) dissolved in sterile normal saline at 0, 6, and 24 h. CD-1suggested: NoneSoftware and Algorithms Sentences Resources The Prism 8.0 statistical software package was used for all statistical calculations (GraphPad Inc, San Diego, CA) Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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