Thread by @ericsongg

Part 2 of SARS-CoV-2 and its effects on the Brain with @ShelFarFar and @VirusesImmunity!

biorxiv.org/content/10.110…
**Highlights**
-Characterization of COVID-19 neuroinflammation
-Indirect evidence of SARS-CoV-2 neuroinvasion
-Evidence of local CNS immunity
#COVID19 #brain 1/n

I am especially proud of this story because we not only describe SARS-CoV-2 neuroinflammation, but also used this opportunity to answer several questions about neuroimmunology that was not explored before. 🧠👏 2/n

We were fortunate to have patient volunteers who allowed us to use some extra clinical lumbar puncture samples to study COVID-19 related neuroinflammation. 3/n

There is a lot of questions around how cytokine storms can affect the brain, so we started with a cytokine panel of matching CSF and plasma from patients. Surprisingly, we noticed that the patients had unique cytokines upregulated in each compartment. 4/n

When we looked at the transcriptional changes using single cell rna seq, we noticed that the cells in the CSF and PBMC were going through unique transcriptional programming; which is expected with such a different environment of the cells 5/n

We noticed that the CSF cells were also increasing in predicted interactions using CellphoneDB from the Teichmann and Vento-Tormo Labs; suggesting that the CNS was harboring a coordinated immune response against something. 6/n

Looking at the T cell populations, we noticed that huge transcriptional changes were occurring in the CSF compartment. 7/n

But interestingly, clonal expansion was seen more in the PBMCs. 8/n

We reasoned that if immune responses against systemic SARS-CoV-2 was globally occurring and the same T cells were affecting both the periphery along with the brain, we would find the same T cells in both compartments. However, this was not always the case. 9/n

This extended to the B cell compartment; where the highest clones of B cells found in the CSF were not the same as the ones found in the PBMC. Actually; there was quite a divergence between the highest represented B cells in each compartment 10/n

Our awesome collaborators (UCSF Wilson lab) mapped out antibodies found in the CSF and Plasma. The current dogma is that circulating antibodies enter the CNS through BBB opening, in which case same antibodies would be found in the two compartments. This was not the case. 11/n

Actually, what we found was that in all the patients, the frequency of different antibodies were quite divergent (interestingly, we found that some epitopes were more enriched in the CNS versus Plasma, see above) 12/n

We finally use our recently developed mouse model to ask the question does CSF antibodies predict CNS infection?

And we were able to show that a localized CNS infection can result in a localized CNS antibody response! 13/n

Once again, this was a huge collaborative effort, as evident by the author list. 14/n

This was an exciting story to navigate as it was inspired by several stories from all over the country ie. @danmucida's work on gut compartments; @jonykipnis's work on CNS-immune circuit and @NareshaSaligra1 @DGateLab @wysscoray's work in using CNS repertoire sequencing 15/n

the take away is:

1. a localized, divergent CNS immune response can occur distinct from the periphery
2. When treating systemic diseases like SARS-CoV-2, we need to consider organ specific treatments (especially for the brain!)

fin/n