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Michalski, Christina

University of British Columbia

Premature birth is a major contributor to under-five mortality, causing approximately 1 million deaths every year. This vulnerability stems from the high susceptibility of neonates, particularly those born prematurely, to severe life-threatening infections. The overarching goal of my thesis work was to study the immunological basis for preterm neonates’ vulnerability to infections. It was previously known that monocytes isolated from preterm cord blood show suppressed responses to innate immune activation. In Chapter 2, we employed untargeted transcriptomics comparing monocytes at rest and after LPS stimulation, from neonates born preterm (<33 weeks gestation), at term (>37 weeks gestation) and from adults. Results establish cellular energy metabolism as a major regulator of innate immune responsiveness during fetal life, perhaps to purposely limit overt inflammation in utero. Additionally, our experiments suggested a central role for mTORC1, and its negative regulator DDIT4L in suppressing innate immune responses in preterm monocytes. In Chapter 3, I developed a monocytic cell line model to study the impact of DDIT4L on innate immune function. DDIT4L overexpression limited protein synthesis, cellular proliferation and LPS-induced cytokine production. Additionally, experiments in primary neonatal monocytes revealed developmental changes in mitochondrial function. Lastly, data linking reduced DDIT4L expression to more severe inflammatory lung disease in preterm neonates point towards a putative role in preventing inflammatory-mediated tissue damage in neonates. Beyond the immediate postnatal period, preterm infants remain particularly vulnerable to respiratory viral infections. In Chapter 4, I studied infants at high-risk for respiratory syncytial virus (RSV) infections. I showed that most infants have been exposed to RSV, as evidenced by increased IgM titers, Fc receptor binding and antibody-mediated phagocytosis by the end of their first winter season. Overall, my study suggests that most high-risk preterm infants develop antibody responses against RSV by one year of age, in the absence of overt clinical signs. This challenges the dogma that preterm infants are unable to fight respiratory illnesses without getting sick and provide insights into the highest period of vulnerability to these viruses. In sum, my work provides fundamental insights into the maturation of immune responses in the first year of life in premature babies.

Text

2023-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80608

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/