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oai:digital.library.adelaide.edu.au:2440/1196682026-06-12T08:09:54Zcom_2440_14759col_2440_14760

Paton, James Amin, Zarina School of Biological Sciences 2017 http://hdl.handle.net/2440/119668 S. pneumoniae is a genetically diverse species which complicates attempts to associate a given clonal lineage or serotype with propensity to cause disease; as well as in the identification of specific molecular determinants of distinct virulence phenotypes. Formation of biofilms is an important step in pneumococcal pathogenesis, as they serve as reservoirs of infection and organisms within biofilms are resistant to antimicrobials and host immune defences. The aim of this work was to extend our understanding of the correlation between biofilm formation in clinical isolates of S. pneumoniae and factors that could influence their invasive disease potential, namely isolate source, pH and Fe(III) supplementation. Firstly, the formation of biofilms of clinical isolates belonging to serotypes/groups 3, 6, 9, 14 and 19 isolated from blood and ear revealed marked inconsistencies in biofilm formation capacity. However, upon MLST typing distinct biofilm phenotypes were identified between blood and ear isolates belonging to the same serotype/group and ST type. Further in vivo investigations on blood and ear isolates of serotype 3 ST180, ST232, ST233 and serotype 14 ST15 revealed distinct pathogenic profiles, which clearly demonstrated the adaptation of the strains to the host niches from which they were isolated. The in vivo co-infection experiment of ST15 isolates further suggested the possibilities of induction of distinct host immune responses, or secretion of a virulence factor by the blood isolate, that prolonged survival of the ear isolate, which would otherwise have been cleared from the lung when challenged in isolation. Investigation of early immune response in the lungs of mice challenged by blood and ear isolates revealed strain-specific differences in gene expression and provided insight into how the immune response may vary from strain to strain, resulting in distinct patterns of infection from two closely related strains. The observed consistent differences suggested the existence of fundamental genomic, methylomic, transcriptomic, proteomic or metabolomic differences between clonally-related blood and ear isolates, which allows them to adapt to, and survive in, distinct host niches. Nevertheless, transcriptomic analysis of the in vitro grown ST180, ST232 and ST15 strains using RNA-Sequencing did not identify any genes that were consistently differentially expressed between the blood and ear isolates of a given ST. This suggests that there may be differences in expression patterns of key virulence-related genes between bacteria growing in different in vivo niches, as well as between in vivo niches and the in vitro cultures. The findings of this study constitute a significant paradigm shift, in that we have found multiple examples of clonally-related strains that consistently and reproducibly exhibit distinct virulence phenotypes in mice that directly correlate with the original site of isolation from human patients (in this case, ear vs blood). Thus, strains within a clonal lineage can exhibit stable niche adaptation. Moreover, our data suggest differential capacity to trigger early host innate immune responses may underpin this adaptation and influence the course of disease. These findings provide a robust platform for future studies aimed at identifying critical bacterial and host determinants of pneumococcal virulence phenotype. Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2017 en Streptococcus pneumoniae biofilms virulence Biofilm formation and virulence of Streptococcus pneumoniae Thesis This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legalsopen.access