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Title: Pneumolysin-macrophage interactions in Streptococcus pneumoniae infection
Author: Malak, H.
ISNI:       0000 0004 6059 2263
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Streptococcus pneumoniae is a common human pathogen that accounts for more than 1 million deaths every year. Nasopharyngeal colonisation by S. pneumoniae is a necessary precursor to pneumonia and invasive disease and, thus, is a promising target for intervention. Pneumococcal virulence factors that maintain long-term carriage are of interest to the improvement of pneumococcal vaccines which currently fail to provide the required protection against >92 known serotypes of S. pneumoniae. The C-type lectin family member mannose receptor (MR) is expressed by macrophages and dendritic cells and has been identified as a non-opsonic receptor for S. pneumoniae in the lung. However, its functional role in pneumococcal infection has not been revealed, nor has its impact on nasopharyngeal carriage been assessed. I used MR-deficient mice and bone marrow derived macrophages to study the role of this receptor in the clearance of S. pneumoniae. Macrophages up regulate MR expression in response to pneumococcal infection both in vitro and in vivo, via a process dependent upon pneumococcal capsular polysaccharides and pneumolysin toxin. Furthermore, MR-expressing macrophages accumulate in the nasopharynx and draining cervical lymph nodes of mice during pneumococcal carriage. MR-/- macrophages are significantly attenuated in their ability to kill S. pneumoniae D39 in vitro and show reduced production of both inflammatory and immunomodulatory cytokines and chemokines, as compared to WT macrophages, in response to S. pneumoniae. MR is required for upregulation of expression of TLR-2 on macrophages in response to pneumococcal infection in vitro and also contributes to the activation of the NLRP3 inflammasome and the production of IL-1ß. Domain four of the pneumococcal toxin pneumolysin binds MR, demonstrating that MR contributes directly to host-pathogen interactions. MR-/- mice have a defect in control of pneumococcal proliferation in the nasopharynx in the first 48 hours post-infection but accumulation of MR+ macrophages in the nasopharynx in wild-type mice takes place over weeks, suggesting a dual role of MR in control of both innate and adaptive immunity. The ability of MR+ macrophages to induce the differentiation of T regulatory cells in vitro suggests that they may contribute to the maintenance of prolonged carriage, in addition to their role in early clearance of colonising bacteria. Proteomic analysis reveals that pneumococcal infection induces a wide range of cellular processes in macrophages, with pro-inflammatory and apoptotic pathways particularly prominent. Macrophages infected with pneumolysin-deficient pneumococci produce high levels of proteins associated with healing and repair and are less geared towards inflammation, demonstrating the ability of pneumolysin to shape immune responses during infection. Taken together, my data add to our understanding of the interactions between S. pneumoniae and the host immune system. MR is a key contributor to macrophage responses against the pneumococcus and pneumolysin is both a crucial virulence factor and an inducer of host immune responses.
Supervisor: Kadioglu, A. ; Neill, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral