The role of IL-17 and IL-22 in the immune response to infection and colonisation with S. pneumoniae

Ritchie, Neil Douglas (2016) The role of IL-17 and IL-22 in the immune response to infection and colonisation with S. pneumoniae. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

Introduction: Streptococcus pneumoniae is an important cause of morbidity and mortality worldwide and a leading cause of pneumonia, bacteraemia and meningitis. Nasal colonisation is a vital prerequisite to disease. Memory T cells and the cytokine IL-17 has been reported to be required for the control of murine nasal colonisation and humans have pneumococcus specific memory T cells but the role of IL-17 in invasive pneumococcal disease remains poorly understood.
Methods: Human pneumococcus specific T cells from peripheral blood using a co-culture model. Young and old adults as well as patients with invasive pneumococcal disease were included. A mouse model of colonisation and disease was used to assess the role of IL-17 and the related cytokine IL-22 in naïve mice using transgenic mice deficient in IL-17 and IL-22 signalling. Data from this model was supplemented with next generation sequencing to investigate the microbiome and prokaryotic transcriptome during colonisation and infection respectively .
Results: Pneumococcal specific memory T cells were identified in human peripheral blood samples and some of these expressed IL-17, IL-22 and interferon-γ following clonal stimulation. IL-17 expressing T cells arose from the CCR6+ subset of T cells. The memory T cell responses of young and old adults were compared. Young adults had greater T cell proliferative in response to pneumococci than old adults and also less expressed more IL-17, IL-22 and interferon-γ.
Two principal models of pneumococcal disease were investigated in animal models. TIGR4 is a highly invasive strain which causes bacteraemia while SRL1 causes severe pneumonia and empyema. RNA-Seq was used to identify differential gene expression in infection relative to growth in broth. Peak IL-17 and IL-22 are production occurs within hours of induction of infection and the likely source of IL-17 was identified as γδ lymphocytes. When IL-17RA-/- mice were infected either strain they demonstrated decreased neutrophil recruitment to blood and lung. TIGR4 infected IL-17RA-/- mice had decreased survival
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whereas SRL1 infected IL-17RA-/- mice had increased survival. TIGR4 is significantly more susceptible to neutrophil phagocytosis than SRL1 in vitro and experiments with mice depleted of neutrophils suggested that neutrophils were important in the survival difference demonstrated between strains. Subsequent studies with a further pneumonic strain (serotype 6B) also demonstrated increased survival in IL-17RA-/- mice. IL-17 was important in the control of nasal colonisation with both TIGR4 and SRL1. The nasal microbiome of IL-17RA-/- mice was significantly less diverse than that of wild type mice with the microbiome dominated by a small number of bacterial species. IL-22-/- mice had impaired resolution of inflammation and increased collagen deposition in lungs following treatment of pneumonia compared to wild type.
Conclusions: IL-17 is an important component of the immune response to pneumococcal disease although it can be either beneficial or harmful depending on the pneumococcal strain and site of infection. Further work will expand on the role of this cytokine in colonisation and disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Streptococcus pneumoniae, pneumococcus, pneumonia, IL-17, IL-22, innate immunity, neutrophils, nasal colonisation.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Bacteriology
Supervisor's Name: Evans, Prof. Tom J.
Date of Award: 2016
Embargo Date: 1 February 2019
Depositing User: Neil D Ritchie
Unique ID: glathesis:2016-7095
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 15 Mar 2017 10:10
Last Modified: 15 Mar 2017 10:39
URI: http://theses.gla.ac.uk/id/eprint/7095

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