Pattern recognition receptor-mediated cytokine response in infants across 4 continents

Abstract

Background: Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination.

Objective: Determine whether differences in innate immune responses exist among infants from different continents of the world.

Methods: We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe).

Results: We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs.

Conclusions: Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world.

Keywords: Innate immunity; global; immune development; infectious disease.

Fig E1

Cytokine production comparison for all 4 sites per cytokine and stimulation. Box-whisker plots, with the median highlighted for each site (the error bars = 90% CI). A, The production of T_H1- and T_H17-supporting innate cytokines. B, The production of the proinflammatory cytokines and chemokines, as well as the regulatory cytokine IL-10.

Fig E1

Cytokine production comparison for all 4 sites per cytokine and stimulation. Box-whisker plots, with the median highlighted for each site (the error bars = 90% CI). A, The production of T_H1- and T_H17-supporting innate cytokines. B, The production of the proinflammatory cytokines and chemokines, as well as the regulatory cytokine IL-10.

Fig E2

Innate immune response to PRR stimulation. PCA ordination of the Poly I:C response is depicted in panel A, PAM in panel B, and MDP in panel C. Each dot represents 1 subject, symbol represents a site, and color represents the stimulation (open [Belgium, Canada, and Ecuador], red [South Africa] for given stimulation).

Fig E3

A simplified vaccine schedule for infants at each site.

Fig 1

PCA ordination of the innate immune response for all subjects measured by cytokine secretion in response to PRR agonists. A, The variance in cytokine response (12 dimensions) to all ligands. Each color represents a ligand, while each dot represents 1 subject. B, Eigenvectors show the particular correlations of individual cytokines to the ordination of the PCA in A.

Fig 2

Innate immune response to PRR stimulation. PCA ordination of the R848 response is depicted in panel A, LPS in panel B, and PGN in panel C. Each dot represents 1 subject, symbol represents a site, and color represents the stimulation (open [Belgium, Canada, and Ecuador], red [South Africa] for given stimulation).