Epithelial responses to pneumococcal capsules drive leukocyte activation and functionality in a serotype-specific manner

Streptococcus pneumoniae (pneumococcus) poses a major disease burden to young children and older adults. About 100 different polysaccharide capsule types (serotypes) have been identified. The capsule is a crucial virulence factor that contributes to pneumococcal immune evasion, and the capsule structure differs per serotype. Some pneumococcal serotypes are associated with invasive disease, while other serotypes are predominantly found in carriage. In this study, we evaluated how the pneumococcal capsule of different serotypes affects epithelial cytokine secretion and ensuing epithelial-mediated leukocyte activation, and functionality. To study the possible effects of the pneumococcal capsule, we infected primary nasal epithelial cells with isogenic capsule mutants of TIGR4 (serotype 4) expressing a serotype 1, 6B, 8, or 35B capsule or no capsule (Δcps). The serotype-specific epithelial cytokines were thereafter analyzed and used to examine their effect on leukocyte activation, migration, and leukocyte-dependent pneumococcal killing. We showed that epithelial cytokine secretion differed per serotype, with the strongest induction after infection with the unencapsulated mutant. Distinct expression profiles of epithelium-induced leukocyte activation markers were observed for each serotype, involving changes in activation marker expression for all investigated cell types. Furthermore, compared with other serotypes, epithelial chemokines induced by serotype 8 reduced neutrophil migration and leukocyte-mediated killing of pneumococci. These data highlight the serotype-specific effect of epithelial cells on leukocyte activation and pneumococcal clearance. The results provide additional insights into serotype-specific differences in the pneumococcal interactions with the mucosal surfaces of the human respiratory tract.IMPORTANCEStreptococcus pneumoniae, also referred to as pneumococcus, poses a major disease burden in young children and older adults, with differences in virulence between serotypes. Little is known about serotype-specific effects on colonization of the upper respiratory epithelial tract. Using isogenic mutants of a single pneumococcal strain expressing capsules of different serotypes, we were able to solely look at the effect of the capsule on epithelium-leukocyte interaction. We found that the various serotypes induced distinct cytokine responses in epithelial cells, and that these epithelial cytokines affected leukocyte activation and their pneumococcal killing capacities. Together with pneumococcal serotype-specific differences in immune evasion described by others, our findings provide additional insights into serotype-specific differences in virulence and help unravel why some serotypes are prone to cause invasive disease while other serotypes are mostly associated with carriage.