Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse
Debby Bogaert1, Daniel Weinberger, Claudette Thompson
1UMC Utrecht-WKZ, Department of Pediatric Immunology, Lundlaan 6 (Room KC.03.069.1), 3584 EA Utrecht, The Netherlands. d.bogaert@umcutrecht.nl
Insights
Neonatal and infant mice show immature immune responses to Streptococcus pneumoniae, similar to human infants. A whole-cell pneumococcal vaccine (WCV) effectively reduces bacterial colonization despite these immune impairments.
Area of Science:
- Immunology
- Microbiology
- Vaccinology
Background:
- Streptococcus pneumoniae colonization and invasive disease incidence are highest in young children.
- Immunity acquired through natural exposure and immune system maturation contribute to declining disease rates.
- A novel mucosal whole-cell pneumococcal vaccine (WCV) with killed pneumococcal antigen (WCA) and cholera toxin adjuvant shows promise, acting independently of antibodies and relying on CD4(+) TH17 cells.
Purpose of the Study:
- To investigate the immune responses of neonatal and infant mice to S. pneumoniae.
- To determine the efficacy of the WCV in neonatal and infant mice.
- To understand the impact of immature immune responses on vaccine effectiveness.
Main Methods:
- Compared nasopharyngeal colonization clearance in infant and adult mice.
- Assessed cytokine production by macrophages from neonatal, infant, and adult mice stimulated with killed pneumococci.
- Evaluated T-cell responses using neonatal and adult macrophages as antigen-presenting cells.
- Measured IL-17A production in response to WCA stimulation in whole blood from neonatally and adult-immunized mice.
Main Results:
- Infant mice exhibited impaired clearance of S. pneumoniae colonization.
- Macrophages from neonatal and infant mice showed reduced pro-inflammatory cytokine production and increased IL-10 compared to adult mice.
- IL-17A production was delayed when neonatal macrophages were used, and WCV-immunized neonates produced less IL-17A than adult-immunized mice.
- A single WCV immunization in neonatal mice significantly reduced S. pneumoniae colonization density.
Conclusions:
- Neonatal and infant mice possess impaired innate and adaptive cellular immune responses to S. pneumoniae.
- Despite immature immune responses, the WCV demonstrates significant efficacy in reducing pneumococcal colonization in neonatal mice.
- The WCV may be effective in young populations with developing immune systems.
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.
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