COVID-19 Prompts Choroid Plexus to Ring Alarm Bell

What does SARS-CoV-2 do to the brains of people with COVID-19? Researchers led by Tony Wyss-Coray, Stanford University, California, and Andreas Keller, Saarland University, Germany, turned to postmortem tissue from severe cases to find out. In the June 21 Nature, they reported that the virus does not seem to weasel its way into the brain. Instead, it provokes choroid plexus cells to relay inflammatory signals to brain cells. Peripheral T-cells flood the brain, microglia and astrocytes adopt transcriptomes similar to those associated with neurodegeneration, and neurons dampen expression of genes that regulate neurotransmission. Could these changes explain COVID brain fog and possibly signal future cognitive problems?

  • No SARS-CoV-2 virus found in postmortem COVID-19 brain tissue.
  • Virus triggered inflammatory responses in choroid plexus and cortical cells.
  • Microglia, astrocytes were activated, upper-layer neurons became dysregulated.

So far, researchers have reported equivocal findings on whether SARS-CoV-2 infects the brain (Jan 2021 news). Regardless, COVID-19 can cause neurological symptoms that may linger for months (Apr 2021 conference news). How they arise, why they linger in some, and what it could mean for long-term cognition remains unknown.

To shed light on what goes awry in the COVID brain, co-first authors Andrew Yang at Stanford and Fabian Kern at Saarland collected postmortem medial frontal cortex and choroid plexus tissue from eight people who had died from COVID-19 and from 14 controls, including one who had died from influenza. They searched for the virus by probing brain tissue slices with three antibodies against the viral spike protein and one against the viral nucleoprotein. Only the anti-spike antibody, dubbed 3A2, bound. “Neuropathologists also saw 3A2 binding in prepandemic brain tissue, indicating that this antibody may not be SARS-CoV-2-specific,” Wyss-Coray told Alzforum. Yang, Kern, and colleagues also found no viral RNA in brain cells via single-nuclei RNA-seq or bulk RNA-seq, nor did they detect it with the quantitative PCR test used for clinical diagnosis. Taken together, they concluded that no virus had entered the brain.  

COVID Postmortem. To figure out what went wrong in severe COVID-19, researchers collected medial frontal cortex and choroid plexus tissue from eight COVID cases and 14 controls. They isolated nuclei, sequenced the RNA, and tested tissue slices to confirm transcriptional changes. [Courtesy of Yang et al., Nature, 2021.]

Then what explains the brain effects in infected patients? To find out, the researchers isolated 38,217 and 27,092 nuclei from the cortex and choroid plexus, respectively, sequenced their transcriptomes, and grouped them by cell type. In cases, endothelial, epithelial, and mesenchymal cells in the choroid plexus upregulated genes involved in complement and interferon pathways, including interferon-induced transmembrane protein 3. IFITM3 is an antiviral defense gene induced by several viruses, including SARS-CoV-2 (Vavougios et al., 2021; Bailey, 2014). The protein is elevated in AD brains and some work suggests it binds γ-secretase to ramp up Aβ production (Sep 2020 news). 

Do the inflamed choroid plexus cells cause harm? The scientists used statistical analyses of the RNA-Seq data to look for upregulated ligand-receptor pairs that might indicate altered signaling pathways. They found that through chemokine signaling, the COVID choroid plexus cells inflamed glia, microglia, and excitatory neurons in the outer layers of the brain.

Transcriptomic profiling bore this out. Subsets of microglia expressed transcripts seen in Alzheimer’s disease-associated microglia. These cells downregulated homeostatic genes and upregulated activation genes (see image below). CD68 staining detected activated microglia in cortical tissue. Similarly, astrocytes from cases ramped up astrogliosis-related genes, and quieted genes in pathways that support synapses and neurotransmission. The researchers compiled their sequencing data for download and analysis into a web app.

DAM COVID. Transcriptomics (left) uncovered a subset of microglia in COVID patients with an altered expression profile (turquoise). They had 41 dysregulated genes in common (right) with disease-associated microglia (DAM). [Courtesy of Yang et al., Nature, 2021.]

Were synapses harmed? Indeed, single-nuclei RNA-Seq revealed fewer neurotransmission-mediating genes in layer 2/3 excitatory neurons, while the number of inhibitory neurons increased. These upper-layer neurons are important for cognitive function. “If COVID-19 survivors have the same neuron perturbations, it would be consistent with brain fog and cognitive complaints,” Yang told Alzforum.

A recent medRxiv preprint analyzing serial MRI scans from 782 UK Biobank participants showed thinning of the cortical surface in those who tested positive for COVID-19 relative to their cortical thickness pre-infection (Douaud et al., 2021).  “The layer 2/3 neurons are near the surface, so it is tempting to say there may be a parallel here, despite studying different brain areas,” Yang commented.

To compare brain changes evoked by COVID to those seen in other diseases, the scientists compared known GWAS risk genes for various neurological conditions to the transcriptional profiles in COVID brain. They found the two states had many genes in common (see image below).

Neurological Overlap. The number of differently expressed genes (dots) from different cell types (bottom axis) found in COVID-19 brain correlated with known GWAS risk genes for various neurological conditions (left axis). Larger circles indicate stronger correlation, while brighter colors mean more genes overlapped. [Courtesy of Yang et al., Nature, 2021.]

All in all, upregulated IFITM3 expression, the appearance of COVID DAMs, and the overlap of altered genes in COVID and other neurological diseases highlights a potential COVID-neurodegeneration nexus. How this relates to the long-term cognitive consequences of COVID-19 infection remains to be seen. “Maybe overlapping symptoms in COVID and AD are both caused by massive neuroinflammation,” said Wyss-Coray.—Chelsea Weidman Burke

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References

News Citations

  1. How Does COVID-19 Affect the Brain?
  2. COVID-19 Worsens Neurological Problems, Delirium
  3. IFITM3 Forges Link Between Neuroinflammation and Aβ Production

Paper Citations

  1. Vavougios GD, Nday C, Pelidou SH, Gourgoulianis KI, Stamoulis G, Doskas T, Zarogiannis SG. Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease. Brain Behav Immun Health. 2021 Jul;14:100243. Epub 2021 Mar 26 PubMed.
  2. Bailey CC, Zhong G, Huang IC, Farzan M. IFITM-Family Proteins: The Cell's First Line of Antiviral Defense. Annu Rev Virol. 2014 Nov 1;1:261-283. PubMed.
  3. Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, Lange F, Andersson JL, Griffanti L, Duff E, Jbabdi S, Taschler B, Winkler A, Nichols TE, Collins R, Matthews PM, Allen N, Miller KL, Smith SM. Brain imaging before and after COVID-19 in UK Biobank. medRxiv June 20, 2021. medRxiv.

External Citations

  1. web app

Further Reading

Papers

  1. Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L, Cheng F. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimers Res Ther. 2021 Jun 9;13(1):110. PubMed.

Primary Papers

  1. Yang AC, Kern F, Losada PM, Agam MR, Maat CA, Schmartz GP, Fehlmann T, Stein JA, Schaum N, Lee DP, Calcuttawala K, Vest RT, Berdnik D, Lu N, Hahn O, Gate D, McNerney MW, Channappa D, Cobos I, Ludwig N, Schulz-Schaeffer WJ, Keller A, Wyss-Coray T. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature. 2021 Jul;595(7868):565-571. Epub 2021 Jun 21 PubMed.

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