Abstract
Neutrophils play an important role in the innate immune response to infection with Streptococcus pneumoniae, the pneumococcus. Pneumococci are phagocytosed by neutrophils and undergo killing after ingestion. Other cellular processes may also be induced, including autophagy and the formation of neutrophil extracellular traps (NETs), which may play a role in bacterial eradication. We set out to determine how these different processes interacted following pneumococcal infection of neutrophils, and the role of the major pneumococcal toxin pneumolysin in these various pathways. We found that pneumococci induced autophagy in neutrophils in a type III phosphatidylinositol-3 kinase dependent fashion that also required the autophagy gene Atg5. Pneumolysin did not affect this process. Phagocytosis was inhibited by pneumolysin but enhanced by autophagy, while killing was accelerated by pneumolysin but inhibited by autophagy. Pneumococci induced extensive NET formation in neutrophils that was not influenced by pneumolysin but was critically dependent on autophagy. While pneumolysin did not affect NET formation, it had a potent inhibitory effect on bacterial trapping within NETs. These findings show a complex interaction between phagocytosis, killing, autophagy and NET formation in neutrophils following pneumococcal infection that contribute to host defence against this pathogen.
Highlights
Streptococcus pneumoniae is a Gram-positive bacterium that is a major cause of community-acquired pneumonia and otitis media, as well as invasive bacteraemia and meningitis
We determined the influence of autophagy on this neutrophil extracellular traps (NETs) formation, using the inhibitor 3MA as well as silencing of the Atg[5] gene (Figure 5). Using both methods (Figure 5b), we found that down-regulation of autophagy significantly reduced NET formation, almost to baseline values, demonstrating that autophagy is essential to NET formation following pneumococcal infection of human neutrophils
Neutrophils play a fundamental role in the innate immune response to pneumococcal infection
Summary
Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium that is a major cause of community-acquired pneumonia and otitis media, as well as invasive bacteraemia and meningitis. Despite antibiotics and vaccine development, the infection remains a highly significant cause of morbidity and mortality worldwide. One of the most important innate defence mechanisms against pneumococci are neutrophils, which rapidly migrate to sites of colonization and infection.[1,2,3] Depletion of neutrophils in a mouse model permits invasive disease to develop, and neutrophil killing of pneumococci contributes to subsequent adaptive immune responses.[4] A number of immunodeficiencies and haematological malignancies associated with neutropaenia are risk factors for invasive pneumococcal disease.[5] Taken together, these findings demonstrate the importance of neutrophils in host defence against pneumococcal infection
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