title: Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model.
abstract: Streptococcus pneumoniae colonization and invasive disease peak around the third and first birthdays, respectively, and decline thereafter. While these declines are attributable in part to immunity acquired via natural exposure, maturation of innate immune responses may also be involved. A mucosally administered candidate whole-cell pneumococcal vaccine (WCV) containing killed pneumococcal antigen (WCA) plus a cholera toxin adjuvant protects against intranasal carriage of pneumococci by a mechanism that is antibody independent and CD4(+) TH17 cell dependent. Because infants and children are a key target population for this vaccine, we sought to evaluate the immune responses of neonatal and infant mice to S. pneumoniae and to assess whether the WCV would be effective in these mice. Like human infants, infant mice showed impaired clearance of nasopharyngeal colonization with S. pneumoniae. Macrophages from neonatal and infant mice stimulated with killed pneumococci in vitro showed significantly reduced cytokine production, including that of KC, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage chemoattractant protein 1, interleukin-6 (IL-6), IL-1alpha, tumor necrosis factor alpha, and gamma interferon, whereas IL-10 expression was significantly increased compared to that in macrophages from adult mice. IL-17A production from adult immune CD4(+) T cells was significantly delayed when neonatal macrophages instead of adult macrophages were used as antigen-presenting cells. Moreover, whole blood from mice immunized as neonates with WCV produced significantly less IL-17A after stimulation with WCA than did blood from mice immunized as adults. Nonetheless, a single immunization of neonatal mice with WCV significantly reduced colonization density. Overall, our data suggest an impairment of both innate and acquired cellular immune responses in neonatal and infant mice. However, WCV confers a significant reduction in colonization following pneumococcal challenge, suggesting that it may still be effective in the setting of immature immune responses.
authors.affiliation: UMC Utrecht-WKZ, Department of Pediatric Immunology, Lundlaan 6 (Room KC.03.069.1), 3584 EA Utrecht, The Netherlands. d.bogaert@umcutrecht.nl
authors.forename: Debby
authors.initials: D
authors.lastname: Bogaert
authors.forename: Daniel
authors.initials: D
authors.lastname: Weinberger
authors.forename: Claudette
authors.initials: C
authors.lastname: Thompson
authors.forename: Marc
authors.initials: M
authors.lastname: Lipsitch
authors.forename: Richard
authors.initials: R
authors.lastname: Malley
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology*; D002353:Carrier State / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007109:Immunity; D007113:Immunity, Innate; D007223:Infant; D007231:Infant, Newborn; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009305:Nasopharynx / Q000276:immunology / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000254:growth & development* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D016207:Cytokines; D022242:Pneumococcal Vaccines