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Title: Mechanisms of pathogenesis of African pneumococcal serotype 1 isolates during nasopharyngeal carriage and invasive disease
Author: Bricio Moreno, L.
ISNI:       0000 0004 6058 8053
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Background: Streptococcus pneumoniae is a human pathogen responsible for serious diseases such as pneumonia, septicaemia and meningitis. There are over 90 pneumococcal serotypes, with serotype 1 being a major cause of invasive disease worldwide. Despite its high invasiveness, serotype 1 is rarely isolated during nasopharyngeal carriage. The aim of this study is to understand the various mechanisms that determine the pathogenicity of serotype 1. Methods: In vitro techniques were used to determine adhesion to and invasion of epithelial cells by serotype 1, and to assess its ability to avoid phagocytosis as well as to uncover the mechanisms involved. Furthermore, two in vivo models of infection in mice were used to assess serotype 1 virulence and ability to colonise and carry in the nasopharynx. Immunological techniques including flow cytometry and enzyme-linked immunosorbent assays were applied to determine the host immune responses to serotype 1. Furthermore, the gene expression of key virulence factors and metabolic pathways was studied in serotype 1 and compared to the less virulent serotype 2 laboratory reference strain D39. Results: Serotype 1 is highly virulent, causing the death of 80-100% of infected mice by 48h post-infection when using an invasive pneumonia model. In a nasopharyngeal carriage model in mice, serotype 1 is able to establish colonisation, although at a lower density and for a shorter period of time than other serotypes. Serotype 1 is not able to induce an early recruitment of T regulatory cells or early production of the cytokines TGF-ß1 and IL-10. The induction of these modulatory cells and cytokines is associated with maintenance of carriage and provides protection to the host during pneumococcal pneumonia. Therefore, the failure to induce immune-modulatory cytokines and regulatory T cells may lead to the clearance of serotype 1 in the nasopharynx and reduced protection against pneumococcal dissemination. Moreover, the gene expression analysis of key virulence factors and metabolic pathways showed that serotype 1 is less adapted to be a successful coloniser but is, in contrast, very successful at becoming invasive. Conclusions: The unique characteristics of the type 1 capsule are likely to influence the immune responses against this serotype; however, differences in the expression of non-capsular determinants may also have a key role in the invasiveness of serotype 1. Although serotype 1 is not successful at maintaining nasopharyngeal carriage, it is highly successful at becoming invasive.
Supervisor: Kadioglu, A. ; Everett, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral