| Summary: | 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. Since innate immunity instructs adaptive immunity, I hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination. To determine if differences in innate immune responses exist among infants from different continents of the world, I investigated the innate cytokine production of whole blood as well as the single cell level response following pattern recognition receptor (PRR) stimulation of blood samples obtained from two-year old infants across four continents (Africa, North America, South America and Europe). I found that despite the many possible genetic and environmental exposure differences in infants between the four cohorts, whole blood cellular components of only South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors (PRR) as compared to whole blood from cohorts of Ecuadorian, Belgian, or Canadian children, specifically following stimulation of extracellular- and endosomal-, but not cytosolic-PRRs. To begin dissection of the responsible molecular mechanisms, I identified the relevant cellular source of these differences. While a significant variation in the cellular composition of whole blood was found, reduction of the intracellular cytokine production on the single cell level was only detected in South African infants’ monocytes, cDC, and pDC. I also uncovered a marked reduction in polyfunctionality for each of these cell types in South African children as compared to children from other continents. Together this data indicates the existence of differences in cell composition as well as profoundly lower functional responses of innate cells in a cohort of South African children. With a difference in number and function of innate immunity in South African children identified, we can now proceed to determine the link between altered innate immunity and increased risk for infection or lower response to vaccines in South African infants. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate
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