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I am a clinician-scientist and developmental immunologist at BC Children's Hospital, UBC (Vancouver, Canada) that conducts discovery research focused mainly on the developing human immune system of newborns and young infants. This includes any research directions that have the potential to translate into therapeutics or improve the health of newborns and young infants. My research is cross-disciplinary, combining clinical (ie. epidemiology, sometimes also interventional methods) and basic science research methodologies at the systems level (eg. "omics").
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2020)
Newborns lack educated adaptive immunity and therefore rely on innate immune defenses to protect themselves from infections. Premature babies are at high risk of severe infections due to the immaturity of their immune system. Umbilical cord blood is readily accessible to study the premature neonate’s immune system, but it does not capture important maturation events that may occur during the neonatal period. The overall goal of my PhD was to investigate the immune system of premature infants during the neonatal period.In chapter 2, I examined the whole blood response to immune stimulation of two prototypic Toll-like receptors: TLR4 and TLR7/8, in preterm infants aged 1-42 days in the neonatal intensive care unit. I identified major functional deficits in pro-inflammatory cytokine levels compared to term cord blood, which were not due to a lack of immune cells. These findings support previous observations made from preterm cord blood studies. To the best of our knowledge, we were the first at the time to study functional TLR responses during this critical development period.In chapter 3, I used RNA-sequencing methods to investigate how these responses are developmentally regulated. Using deconvolution algorithms, I found that preterm cord blood is distinct from preterm postnatal blood and term cord blood, with a gradual transition from an immature immune system enriched in hematopoietic stem cells, myeloid and erythroid progenitor cells, to a more mature immune cell composition in term cord blood. I also provide the first data directly linking immaturity of the preterm immune system to the risk of sepsis. In chapter 4, I examined innate-like characteristics of naïve CD4 T cells in term cord blood, as a means whereby newborns may compensate for a lack of adaptive memory immune cells. I demonstrate that activation of the antigen presenting cell is important to enhance innate-like IL-8 production in naïve CD4 T cells. The work within this thesis further characterized the immune function of newborns across the gestational age spectrum, providing novel insights into their immune development and factors underlying the high susceptibility of premature infants to infection.
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.