Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2019)
No abstract available.
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 all 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 factors regulating immune responses in the highly genetically diverse human population, providing insight into the development of these pathways in the late fetal/early neonatal period, and support a major role for metabolism in regulating immune reactivity in the general population and during ontogeny.
Almost four million neonates die of infectious and prematurity-related causes across the world annually. The innate immune system provides evolutionarily ancient first-line protection against most microbial pathogens. In contrast, the adaptive immune system is capable of developing an immunological memory that provides enhanced protection in vertebrates. A mechanistic understanding of the maturation of the human preterm neonatal immune system is lacking and this may limit our ability to develop more age-appropriate immunological therapies. In Chapter 1, I analyzed prototypic anti-microbial receptor responses in a clinically well-characterized cohort of premature infants to provide evidence that responses develop asynchronously and follow a developmental pattern that is independent of perinatal factors linked to the premature delivery. In Chapter 2, I dissected molecular rate-limiting steps along a major inflammatory pathway leading to the production of the interleukin-1β (IL-1β) cytokine, across development. The IL-1β cytokine is particularly important as its production serves to amplify innate immune responses. I show that premature neonates born early in the third trimester of gestation lack IL-1β responses due to a lack of activity in the caspase-1 enzyme. In the final chapter, I developed an efficient purification method to study the phenotype of neonatal invariant Natural Killer T (iNKT) cells. Using this method, I show that neonatal iNKT cells display heightened proliferative capacity compared to conventional T cells, consistent with an innate-like phenotype. Altogether, my work provides important insights into mechanisms and developmental characteristics of the fetus and early newborn immune system. This work forms the basis for future studies aimed at understanding how functional characteristics of the neonatal immune system can be therapeutically modulated to prevent neonatal infections.
Master's Student Supervision (2010 - 2018)
One of the body’s most vital functions lies in its ability to fight off invasions from microbes. Preterm neonates born less than 32 weeks of gestation represent the highest-risk patient group in terms of morbidity and mortality resulting from infections. However, data about the function of the immune system of preterm infants is deeply lacking.The interleukin-1-beta pro-inflammatory cytokine is a powerful pyrogen and inflammatory mediator implicated in several preterm diseases. IL-1-beta is produced as a precursor protein (pro-IL-1-beta) following the trigger of Toll-like receptors and secreted upon cleavage by Caspase-1 within the multi-protein NALP3 inflammasome complex.We sought to investigate early life developmental regulation mechanisms by which the production and secretion of IL-1-beta is limited before term of gestation. Our data show that preterm neonatal cord blood (CD14+) monocytes are substantially impaired in their ability to secrete IL-1-beta upon stimulation of Toll-like receptors using lipopolysaccharide. Using flow cytometry, we confirmed sufficient accumulation of the intracellular pro-IL-1-beta precursor protein in preterm cord blood monocytes. However, caspase-1 activity was markedly decreased in infants born before 29 weeks of gestation and was undetectable in some preterms born at the beginning of the second trimester (~24+ weeks), leading to an impaired cleavage and secretion of pro-IL-1-beta.Our data reveal a major mechanism responsible for the attenuation of inflammation before the term of gestation. This developmentally-regulated inhibition of Caspase-1 activity may be an important mechanism to prevent potentially harmful excessive inflammatory responses in early life.