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SARS-CoV-2 infects brain choroid plexus and disrupts the blood-CSF-barrier

Laura Pellegrini, Anna Albecka, Donna L. Mallery, Max J. Kellner, David Paul, Andrew P. Carter, Leo C. James, Madeline A. Lancaster

Preprint posted on August 21, 2020 https://www.biorxiv.org/content/10.1101/2020.08.20.259937v1

Selfless but not harmless: SARS-CoV2 opens the gate to the brain. New insights from choroid plexus organoids.

Selected by Theresa Pohlkamp

Background

Half a year ago, the WHO declared the COVID-19 outbreak caused by SARS coronavirus 2 (SARS-CoV2) a pandemic. Severe respiratory symptoms are usually the reason for hospitalization and can cause pneumonia and other secondary effects like organ failure that sometimes lead to death. However, most infected individuals only present with cold/flu-like symptoms. One of the most common mild symptoms is loss of smell, indicating implications with the central nervous system. Other common neurological symptoms are dizziness, fatigue, and headache. Even though less common, these symptoms can become chronic and in rare scenarios neurological complications like encephalitis, stroke, micro-hemorrhage, or seizures occur. The preprint by Pellegrini et al. sheds light on the mechanism how the virus affects the integrity of the barrier between circulating blood and the cerebrospinal fluid (CSF). The findings are an important step towards future therapeutic strategies to ease the burden of neurological consequences in COVID-19 patients.

To enter its host cell, the virus binds with its so-called spike protein, which decorates its envelope, to the ACE-2 receptor of host cells. ACE-2 is commonly expressed on epithelial-type and smooth muscle cells of several visceral organs. Thus, once SARS-CoV-2 is present in the circulating blood, it can spread through the body easily. The choroid plexus (ChP) is a layer of epithelial cells interconnected through tight junctions, which provides a protective barrier between circulating blood and CSF, while also producing CSF. The CSF is partly de novo secreted and partly ultrafiltrated plasma and contained within the ventricles of the brain.

Pellegrini et al. found that a specific type of lipoprotein-producing ChP epithelial cells is infected and destroyed by SARS-CoV2. Even though they did not identify neurons as a likely virus-target, a leaky ChP allows harmful substances to enter the brain from the circulation and might be the culprit of neurological complications that occur in COVID-19 patients.

 

What was done?

The authors re-analyzed their own recently published single-cell RNAseq data of human telencephalic and ChP organoids (artificial mini organs grown in a dish) (Pellegrini et al., 2020) to identify cell cluster that express ACE-2 and SARS-CoV2 co-entry factors. They found high receptor expression in the ChP but not the telencephalic organoids. More specifically, they identified a specific subtype of ChP cells highly expressing ACE-2. According to their gene expression profile, they classified this subtype as lipoprotein-producing. In a next step, they infected the organoids with the virus. Indeed, infection with SARS-CoV2 was much more successful in ChP than in telencephalic organoids. Neurons within the telencephalic organoids, which comprise excitatory and inhibitory neurons, were not the target of SARS-CoV2, unless an non physiologically high virus load was applied. Most strikingly, the authors found that SARS-CoV2 infection of the ChP disrupted tight junctions within two days (Figure), and caused massive tissue damage after two additional days. Consequently, SARS-CoV2 infects and damages the ChP and abolishes its function as a gatekeeper. Consequently, the CSF gets contaminated with toxins, cytokines, pathogens and immune cells of the circulating blood. Ventricular CSF freely diffuses through the ependymal cell layer to reach all brain cells including neurons and glia; thus, they are now exposed to harmful biomolecules from the circulation.

 

Figure. SARS-CoV-2 disrupts ChP epithelial integrity. Staining for tight junction protein Claudin 5 in ChP epithelium infected with SARS-CoV-2 or mock. Clearly demarcated junctions (arrows) are present in mock but not SARS-CoV-2 infected ChP. Green signal in mock is nonspecific background. Reproduced with permission from Figure 4G of the preprint.

 

 What I like about this study and how I connect it to a protein I study in my research, Apolipoprotein E (ApoE)

The initiation of the study is based on the analysis of single cell RNAseq data of a novel ChP organoid system developed by the authors and very recently published in Science (Pellegrini et al., 2020). It is exciting to see how tracing the ACE-2 receptor leads to such an important insight about how SARS-CoV2 affects the barrier between blood and the CSF. Another recent preprint on SARS-CoV2 and neurotropism confirms cell death of ChP cells and reports rare infection of neurons and astrocytes, but no infection of microglia (Jacob et al., 2020). Since my work focuses on the function of lipoproteins and their receptors in the brain, it strikes me that the type of ChP cells primarily infected by SARS-CoV2 is specialized on lipoprotein expression. Among the apolipoproteins enriched were ApoA, ApoB, and ApoE.

In May researchers identified ApoE isoform ε4 (ApoE4), a genetic Alzheimer’s disease risk factor, as a vulnerability factor for severe COVID-19 (Kuo et al., 2020). There is evidence that in humans ApoE4 genotype contributes to blood brain barrier dysfunction (Montagne et al., 2020). In mice, ApoE also plays a functional role in the ChP to keep inflammation in check. Moreover, ApoE4, but not ApoE3 (the more common allele in humans) expressing mice develop abundant lipid deposits in the ChP, when on a high-fat diet (Yin et al., 2019). In another mouse-based study, human ApoE3 and ApoE4 isoforms had a different effect on SARS-CoV2 Spike-protein uptake in various organs, but not the brain (Rhea et al., 2020). However, Spike-uptake is not necessarily comparable with SARS-CoV2 infection, and mouse and human tissue might respond differentially. For future studies it would be important to examine the condition of the ChP of postmortem COVID-19 patients. Next, it would be interesting to understand if and how pre-conditions like obesity and diabetes contribute to ChP integrity. In addition, ChP organoids with different ApoE-genotype could be explored.

 

My questions to the authors

  1. Did you or someone else look at postmortem brain tissue of COVID-19 patients to examine the condition of the ChP epithelium?
  2. Since lipoprotein expressing cells seem to be the weak spot in the ChP, how do you think metabolic diseases such as obesity and diabetes affect the integrity of the ChP after SARS-CoV2 infection?
  3. Is there a study that looks at ApoE genotype among COVID-19 patients with chronic neurological complications?
  4. What was the ApoE genotype of the ChP organoids?

 

References

Jacob, F., Pather, S.R., Huang, W.-K., Wong, S.Z.H., Zhou, H., Zhang, F., Cubitt, B., Chen, C.Z., Xu, M., Pradhan, M., Zhang, D.Y., Zheng, W., Bang, A.G., Song, H., Torre, J.C. de a, Ming, G., 2020. Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism. bioRxiv 2020.07.28.225151.

Kuo, C.-L., Pilling, L.C., Atkins, J.L., Masoli, J.A.H., Delgado, J., Kuchel, G.A., Melzer, D., 2020. APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. J. Gerontol. A Biol. Sci. Med. Sci.

Montagne, A., Nation, D.A., Sagare, A.P., Barisano, G., Sweeney, M.D., Chakhoyan, A., Pachicano, M., Joe, E., Nelson, A.R., D’Orazio, L.M., Buennagel, D.P., Harrington, M.G., Benzinger, T.L.S., Fagan, A.M., Ringman, J.M., Schneider, L.S., Morris, J.C., Reiman, E.M., Caselli, R.J., Chui, H.C., Tcw, J., Chen, Y., Pa, J., Conti, P.S., Law, M., Toga, A.W., Zlokovic, B.V., 2020. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76.

Pellegrini, L., Bonfio, C., Chadwick, J., Begum, F., Skehel, M., Lancaster, M.A., 2020. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 369.

Rhea, E.M., Logsdon, A.F., Hansen, K.M., Williams, L., Reed, M., Baumann, K., Holden, S., Raber, J., Banks, W.A., Erickson, M.A., 2020. The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation. bioRxiv 2020.07.15.205229.

Yin, C., Ackermann, S., Ma, Z., Mohanta, S.K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., Bontha, S.V., Srikakulapu, P., Beer, M., Megens, R.T.A., Steffens, S., Hildner, M., Halder, L.D., Eckstein, H.-H., Pelisek, J., Herms, J., Roeber, S., Arzberger, T., Borodovsky, A., Habenicht, L., Binder, C.J., Weber, C., Zipfel, P.F., Skerka, C., Habenicht, A.J.R., 2019. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat. Med. 25, 496–506.

 

 

Posted on: 18th September 2020

doi: https://doi.org/10.1242/prelights.24763

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