XClose

UCL Great Ormond Street Institute of Child Health

Home

Great Ormond Street Institute of Child Health

Menu

Establishing the Aetiology of PIMS-TS Paediatric Multisystem Inflammatory Syndrome

Supervisors: Dr Louis Grandjean, Professor Nigel Klein, Dr Susannah Felsenstein

Establishing the Aetiology of PIMS-TS Paediatric Multisystem Inflammatory Syndrome Temporally Related to COVID

Background:
More than 125 patients with severe inflammation and hypotension following infection with SARS-CoV-2 have been admitted to Great Ormond Street Hospital over the last year. Although the clinical syndrome has been defined as PIMS-TS (Paediatric Multisystem Inflammatory Syndrome Temporally Associated with SARS-CoV-2) the aetiology of this condition is still poorly understood. This lack of knowledge limits the development of appropriate treatments. Our group and others1 have established that a large proportion of patients with PIMS-TS inflammation have a very unusual T-cell expansion in V-Beta 21.3 that may be driven by a super antigen effect. This PhD seeks to characterize precisely what is underlying this highly unusual pattern of T-cell mediated inflammation that we are observing in PIMS-TS.

Aims/Objectives:
To define the aetiology of PIMS-TS, specifically:
1. To characterise the immunology of the PIMS-TS T-cell expansion by applying Mass Spectrometry to sorted PIMS-TS V-Beta 21.3 T-cells.
2. To undertake T-cell receptor alpha and beta chain sequencing of PIMS-TS patients and compare this to appropriate controls. This will establish the clonality or polyclonality of the T-cell receptor.
3. To work with Google Deep Mind to establish the structure of PIMS-TS specific T-cell receptors and thereby identify whether there is a complementary super antigen either on the SARS-CoV-2 genome or elsewhere in the global epitope databases.

Methods:
We have routine clinical samples stored from ~60 PIMS-TS patients suitable for analysis. Together with the Mass Spectroscopy Department and the Flow Cytometry department, PIMS-TS T-Cells will be sorted and undergo TCR sequencing and Applied Mass Spectrometry evaluation of the V-Beta 21.3 inflammasome to characterise the genetic basis of PIMS-TS and the inflammatory milieu. The latest in conformational protein folding algorithms will be employed in a collaboration with Google Deep Mind in order to establish the structure of the PIMS-TS T-cell receptor and whether or not this matches known epitopes. Establishing the mechanisms of PIMS-TS will enable us to develop treatments and new diagnostic tests for the condition.

Timeline:
Month 1-12: Training in flow cytometry, analysis of mass spectrometry data and bioinformatics at UCL
Month 12-24: Undertaking sample processing and analysis
Month 24-36: Write up and publication of the data 

References:
Marion Moreews et al. Superantigenic TCR Vbeta 21.3 signature in Multisystem Inflammatory Syndrome in Children doi: https://doi.org/10.1101/2021.02.11.21251166