IL-17 can be protective or deleterious in murine pneumococcal pneumonia

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains.
Author summary Streptococcus pneumoniae (the pneumococcus) is an important human pathogen and the commonest cause of community-acquired pneumonia. The bacterial carbohydrate capsule is a key determinant of virulence and host defence. Pneumonia follows colonization of the nasopharynx and can spread systemically. The cytokine IL-17, a key regulator of neutrophil host defence, is important in preventing colonization but its effects on pneumococcal pneumonia are not known. Here, we show that IL-17 has differing roles in host protection against pneumococcal pneumonia that depend on bacterial strain and capsule thickness. Pneumococci with thin capsules invade rapidly and IL-17 is protective; in strains with large capsules that remain in the lungs, IL-17 is detrimental. These strains evade neutrophil killing, and depletion of neutrophils improves outcome following infection. Thus, neutrophil accumulation within the lung is deleterious in pneumonia caused by heavily encapsulated pneumococcal strains. Our study provides fresh insight into the role of IL-17 in host defence against pneumococcal pneumonia, which may also be relevant in other infections caused by encapsulated bacteria that colonize before infection, such as the meningococcus and Haemophilus influenzae.