Recognition and clearance of Streptococcus pneumoniae by the innate immune system.
Streptococcus pneumoniae (the pneumococcus) is a major human pathogen causing diseases such as pneumonia, bacteremia or meningitis and constitutes a leading cause of morbidity and mortality worldwide. The pathogenesis of pneumococcal disease and the mechanisms of recognition and clearance of S. pneumoniae by the immune system are incompletely understood.
Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system and play an important role in host defense against invading microbes. Pattern recognition receptors are present on many cell types such as macrophages and neutrophils. Neutrophils are cells of the innate immune system that engulf and subsequently kill microbes intracellularly through antimicrobial granule components and reactive oxygen species. Recently, neutrophils were shown to form neutrophil extracellular traps (NETs), extracellular filamentous structures consisting of DNA and bactericidal granule proteins. NETs can trap and kill microbes extracellularly at sites of infection and comprise a novel mechanism of innate host defense.
The aim of this thesis was to study the role of Toll-like receptors, NETs and the granule contents of neutrophils in their interaction with S. pneumoniae. Host-pathogen interactions were assessed both in vivo in different murine models of pneumococcal disease and in vitro, employing isolated cells and killing assays. The bacterial and host factors influencing recognition and clearance were studied, employing knockouts in bacterial as well as host genes.
We found that TLR9, but not TLR1, TLR2, TLR4, TLR6 or the IL-1/IL-18 receptor pathway plays a non-redundant role in host defense against S. pneumoniae. Furthermore, TLR9 is essential for the early pulmonary defense against pneumococci and plays a role in phagocytosis of S. pneumoniae by alveolar macrophages. NETs are formed in the lungs of mice with pneumococcal pneumonia and pneumococci are trapped in NETs. S. pneumoniae has evolved at least three virulence factors to counteract the action of NETs. The surface-bound DNase EndA allows pneumococci to degrade the DNA scaffold of NETs. Thereby bacteria can free themselves from entrapment in NETs. In vivo, DNase expression promotes spreading of pneumococci from the upper airways to the lungs and from the lungs into the bloodstream during pneumonia. The pneumococcal polysaccharide capsule limits trapping by NETs. Capsule and D-alanylation of pneumococcal surface structures act together to render the organism resistant to killing by antimicrobial components present in NETs. From a neutrophil granule extract we identified α-defensins as antimicrobial peptides that efficiently kill encapsulated virulent pneumococci. We found that non-encapsulated pneumococci were more resistant to α-defensins and that this resistance is mediated mainly by D-alanylation of pneumococcal surface structures.
In conclusion, we could contribute to further elucidate the processes underlying recognition and clearance of pneumococci by the innate immune system. We identified TLR9 as a non-redundant receptor for the early recognition and clearance of S. pneumoniae by alveolar macrophages and found that neutrophils with their antimicrobial components and NETs play a crucial role in host defense against pneumococci. This importance is underlined by the fact that S. pneumoniae has evolved several virulence factors to evade NETs and neutrophil killing.
List of scientific papers
I. Albiger B, Dahlberg S, Sandgren A, Wartha F, Beiter K, Katsuragi H, Akira S, Normark S, Henriques-Normark B (2007). Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection. Cell Microbiol. 9(3): 633-44. Epub 2006 Sep 27
https://pubmed.ncbi.nlm.nih.gov/17004992
II. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, Henriques-Normark B (2006). An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr Biol. 16(4): 401-7
https://pubmed.ncbi.nlm.nih.gov/16488875
III. Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, Normark S, Henriques-Normark B (2007). Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol. 9(5): 1162-71. Epub 2007 Jan 9
https://pubmed.ncbi.nlm.nih.gov/17217430
IV. Beiter K , Wartha F, Hurwitz R, Normark S, Zychlinsky A, Henriques Normark B (2007). The capsule sensitizes Streptococcus pneumoniae to neutrophil alpha-defensins HNP 1-3. [Submitted]
History
Defence date
2008-01-18Department
- Department of Microbiology, Tumor and Cell Biology
Publication year
2008Thesis type
- Doctoral thesis
ISBN
978-91-7357-342-9Number of supporting papers
4Language
- eng