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Title: Monitoring immune dynamics following infection and vaccination using B cell receptor sequencing
Author: Petrova, Velislava
ISNI:       0000 0004 7231 6346
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Sequencing B and T cell receptor genes allows for detailed characterisation of the genetic diversity underlying adaptive immune responses in health and disease. In the context of infectious diseases this can act as a powerful tool for identification of pathogen-specific immune signatures and genetic determinants of immune memory, protection and response to re-exposure. As part of my PhD I developed and optimised a method for high-resolution profiling of B cell receptor (BCR) immune repertoires based on the barcoded sequencing of the human immunoglobulin genes. The use of molecular barcodes allowed for reduction of technical noise, which can lead to erroneous assignment of lymphocyte function. I applied this methodology to the study of natural infection with measles virus in unvaccinated children. Childhood measles causes a profound immune suppression, which can last for weeks to months post infection, with large reductions in numbers of circulating B cells. Interestingly, long-term consequences of measles immune suppression result in increased incidence of secondary infections up to 3 years after resolution of measles. Vaccination against measles virus with the MMR vaccine has been a major factor in reducing direct and secondary childhood morbidity and mortality. The maintenance of sufficient global vaccine coverage, however, has been challenging due to the refusal of vaccination, mainly in religious communities, resulting in increasing number of outbreaks worldwide. In addition to the overall drop in measles virus herd immunity, measles-induced immune suppression can compromise immunity to other infectious pathogens, thus complicating global vaccination and surveillance efforts. The exact mechanisms underlying the prolonged immune-suppression associated with measles remain elusive and have not been investigated in humans. I applied BCR sequencing to characterise the long-term immunological effects of natural measles virus infection in a cohort of unvaccinated children. Specifically, I addressed the restructuring of immune memory and the possible loss of immunity to non-measles pathogens. My work provided evidence for previously hypothesised depletion of B cell memory pools, referred to as ‘immunological amnesia’. Loss of clonally expanded B memory populations lead to immune re-setting and convergence in repertoire diversity between measles-infected and control groups. In addition to the loss of individual-specific variation in immune memory, a subset of measles-infected individuals exhibited dramatic collapse in the diversity of their naïve B cell compartment, despite the recovery of normal B naïve cell counts. An effect of measles on serological immunity was also demonstrated in a ferret model of measles, where lymphotropic challenge lead to significant loss of vaccine-acquired immunity to influenza virus. The work presented in this dissertation demonstrates the utility of BCR sequencing for understanding adaptive immune responses in the context of infectious diseases and highlights the potential of this approach to uncover novel mechanisms of immune (dys)function.
Supervisor: Anderson, Carl ; Russell, Colin ; Kellam, Paul Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: immunology ; genomics ; sequencing ; vaccination ; viruses ; leukemia