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Jeffreys, Bethan (2021) Identification of potential therapeutic targets for Streptococcus suis infection. MRes thesis, University of Nottingham.

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Abstract

Streptococcus (S.) suis is a commensal porcine pathogen that is the leading causative agent of bacterial meningitis and sepsis in young pigs globally. Systemic infection in swine is associated with considerable mortality and has significant animal welfare and economic consequences. This zoonotic pathogen causes similar clinical pathology in humans as seen in pigs, which can result in life-changing post-streptococcal sequelae. S. suis is recognised as an emerging zoonotic disease and is the primary cause of meningitis in human adults in South East Asia, with two recent outbreaks in China manifesting as Streptococcal toxic shock-like syndrome in patients. The virulence mechanisms by which S. suis transitions from a commensal species within the nasopharynx and tonsillar microflora to a pathogenic species

proliferating within host blood and disseminating into peripheral organs and the brain are still largely unknown. Proposed virulence mechanisms are often extrapolated from current knowledge about the pathogenesis of similar infections caused by Group A and Group B Streptococci. Whilst S. suis infections are readily treatable with β-lactam antibiotics, reports of antimicrobial resistance are increasing and driving the need for alternative therapeutics with novel targets and mechanisms of action. Maintaining effective treatment options are critical as the genetic diversity of serotypes within the S. suis strain population has meant that an effective commercial vaccine has yet to be developed. Establishing a more comprehensive understanding of the mechanisms of S. suis pathogenesis must be achieved to identify molecular targets for novel therapies and diagnostic tools.

Transposon mutagenesis is frequently used in bacteriology to identify genes which are associated with increased fitness or essential for life. The Pragmatic Insertional Mutation Mapping System is a mapping-based tool which utilises the mutagen pG+host::ISS1 to identify essential genes in Gram-positive species in varying growth conditions. The PIMMS protocol was successfully used to elucidate genes which were essential for the growth of S. suis P1/7 in Brain-Heart Infusion (BHI) media with the addition of hydrogen peroxide (H2O2) to model a phagocytic respiratory burst in vitro. In total, 160 genes were identified as being essential for general survival and growth in media. Of these, functional annotation revealed that the majority of genes were associated with basic cellular functions including metabolism and information processing. Further analysis revealed that several genes were associated with the cell division cycle and the signal recognition particle pathway. A total of 35 genes were identified as important for survival and growth in the presence of H2O2. Statistical analysis revealed that a switch from carbohydrate metabolism to general metabolism occurred in the transition from the BHI to the H2O2 environment, evidenced by an overrepresentation of genes associated

with general metabolism in the H2O2 phenotype. Genes associated with alternative metabolic pathways in the presence of H2O2 and the direct and indirect expression and secretion of 3 virulence factors were identified following further investigation. The FtsEX, complex, FtsY, Fhs, FolD, CcpA, SecE, putative signal peptidase I (SSU0212), OppD and putative haemolysin-III (Hly-III) (SSU0854) were identified as having promising novel therapeutic or diagnostic potential which require greater investigation and may be utilised in the control of future S. suis infections.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Egan, Sharon Blanchard, Adam Leigh, James
Keywords:	Streptococcus, pathogens, zoonoses
Subjects:	Q Science > QR Microbiology > QR 75 Bacteria. Cyanobacteria S Agriculture > SF Animal culture
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	65803
Depositing User:	Jeffreys, Bethan
Date Deposited:	04 Aug 2021 04:43
Last Modified:	04 Aug 2021 04:43
URI:	https://eprints.nottingham.ac.uk/id/eprint/65803

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