Immune Transcriptome and B cell receptor repertoire in COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in Coronavirus disease 2019 (COVID-19) was declared by the World Health Organization a global pandemic on March 11, 2020. SARS-CoV-2 primarily infects respiratory epithelial cells, and results in a range of clinical manifestations from asymptomatic disease to multi-organ failure. We studied the immune response of SARS-CoV-2-infected individuals with a range of severities followed over 2- 6 months from symptom onset. We undertook deep immune-phenotyping and transcriptomic analysis. We demonstrated that an early robust immune response, without systemic inflammation, was characteristic of asymptomatic or mild disease. Immune recovery was complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. In addition, we performed B cell receptor repertoire analysis of SARS-CoV-2 infected individuals and recipients of SARS-CoV-2 vaccine. B cells play a central role in the immune response to both SARS-CoV-2 infection and vaccination. We found marked differences in the global BCR repertoire after natural infection compared to vaccination. Following infection, the proportion of BCRs bearing IgG1/3 and IgA1 isotypes increased, somatic hypermutation (SHM) was markedly decreased and, in patients with severe disease, expansion of IgM and IgA clones were observed. In contrast, after vaccination the proportion of BCRs bearing IgD/M isotypes increased, SHM was unchanged and expansion of IgG clones was prominent. Infection generated a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein whilst vaccination produced a more focused response mainly targeting the spike’s receptor-binding domain. These findings offer insights into how different immune exposure to SARS-CoV-2 impacts upon BCR repertoire development, potentially informing vaccine strategies.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Kotagiri, Prasanti

Advisors dc:contributor.advisor

• Smith, Ken
• Lyons, Paul

• SARS-CoV-2
• BCR repertoire
• Transcriptomics

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.85391

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/337984