Thread by @ArditiMd

Ivet Bahar and our labs with the brilliant scientists in both labs worked very hard for this paper. pnas.org/content/early/… 1- SARS-CoV-2 spike harbors a high affinity site for TCR β-chain binding, which contains an insertion, P681RRA684, unique to SARS2. @EricTopol #COVID19

2- Comparison to other β-CoV S sequences showed that SARS-CoV-2 S is distinguished by the existence of this 4-residue insertion, PRRA, preceding the S1/S2 cleavage site (R685-S686 peptide bond) (Fig.2A). The insertion PRRA and sequence similarities to those of neurotoxins Fig.2D.

3-Further examination of the motif near PRRA reveals close structural similarity to the Staphylococcus Enterotoxin B i.e. SEB superantigen as well as sequence similarities to neurotoxins and a viral SAg. All IVIG batches contain high anti SEB neutralizing Abs

4- An ICAM-1 like motif shared between SARS1 and SARS-CoV-2 spikes interacts with TCRVα to further stabilize the S-TCR complex.

5-A neurotoxin-like fragment at the RBD may also bind αβTCR thus further enhancing the immune response. Potentially explaining the neurologic findings? Overall, this neurotoxin-like sequence T299-Y351 deserves attention as a possible source of CNS disorders in COVID-19 patients.

6- TCR repertoire analysis shows TCRVβ skewing & junctional diversity in severe COVID19 adults. Together, our results suggest expansion of TCRs using distinct V genes, along with J gene/CDR3 diversity in these rearrangements, compatible with a SAg selection process.

7- Finally we show that TCRs corresponding to TRVB genes activated in severe COVID-19 patients can bind the SAg-like region of SARS-CoV-2 S as well as to MHCII by using structurally resolved TCRs that contained these enriched Vb chains. Suppl Fig 8.

8- In summary, we made five major observations: (a) PRRAR and sequential neighbors interact with TCRVβ residues D56, R70 and E74 at the CDRs, and this association closely resembles that of SEB SAg with TCRVβ;

9- b) A rare mutation, D839Y/E, recently observed in a SARS2 strain from Europe may contribute to stabilizing the interaction with TCRVβ;

10-c) a sequence motif (N280-T286) typical of ICAM-1 interacts with the TCRVα further stabilizing the association between the spike and host cell TCR;

11-(d) a neurotoxin-like motif (T299 - Y351) shows a high tendency to bind TCRs and potentially trigger neurotoxic responses. This latter effect may be attenuated if the SARS-CoV-2-infected individual has been exposed HCoVs that contain homologous segments.

12-(e) adult patients with severe/hyperinflammatory COVID-19 exhibit a skewed TCR Vβ repertoire distinguishing them from patients with mild/moderate COVID-19.

13-Overall, our results from both computational modeling and NGS immunosequencing of TCRBs analysis of human samples indicate that strategies used for the treatment of SEB-mediated TOxic Shock syndrome or

14- approaches to block the interaction of the S protein with TCRs may help reduce hyperinflammatory manifestations such as MIS-C and cytokine storm or (neuro)toxic effects of COVID-19 in both adults and children.