Innate immunity is the first line of defense against infection, and is particularly important in newborns, as they lack immunological memory. During fetal development, innate immunity must be carefully regulated to prevent miscarriage. In contrast, upon reaching term, the innate immune system of the newborn must rapidly become operational to provide protection against exposure to the extra-uterine microbial environment. Human immune responses are generally highly variable among individuals of

more »

... l ages. According to current models, immune reactivity is highly influenced by an individual's genetic make-up. However, studies in my thesis suggest that immune reactivity is also drastically influenced by non-genetic factors. My overall goal during my PhD was to understand the mechanisms regulating innate immune reactivity in humans, across the development spectrum, to better understand why some individuals are more susceptible to significant clinical infections. I hypothesized that examining responses at the systems level would inform me on how innate immune reactivity is regulated throughout life. Candida species (spp) are common neonatal pathogens. Despite the clinical importance of these pathogens, relatively little is known about the maturation of anti-fungal innate immune defenses in newborns. In Chapter 2 of my thesis, I examined innate immune responses to Candida spp. in preterm infants. I discovered that cellular metabolism plays a major role in regulating immune reactivity during fetal life, via regulation of protein translation. In Chapter 3 of my thesis, I applied similar methods to understand the factors driving the variability in innate immune responses in healthy adults. As expected, I found a large diversity in immune responses between individuals. Surprisingly, some of these protein level responses were largely independent of gene transcription events. I provide evidence that metabolic pathways also modulate immune reactivity in healthy adults. Overall, my findings enhance our understanding of the f [...]