UBC Theses and Dissertations
Ontogeny of cytokine respones following cytoplasmic pattern recognition receptor stimulation Bedi, Harjot Kaur
The innate immune system of newborns is biased towards the production of cytokines that are largely anti-inflammatory or promote development of Th2- and Th17-type of immunity, i.e., an immune response focused against pathogens in the extracellular milieu, and in particular, mucous membranes. This leads to an increased susceptibility to infections by intracellular pathogens, whose clearance depends primarily on effective cell-mediated Th1-type immunity. These insights were gleaned from the analysis of cytokines produced in neonatal and infant blood in response to Toll-like receptor (TLR) stimulation. However, TLRs are only one of the classes of a broader repertoire of molecules called pattern recognition receptors (PRRs). To our knowledge, PRRs that are specialized for the detection of intracellular pathogens – namely, cytoplasmic PRRs – have not been systematically and comprehensively analyzed in the context of the newborn immunity. Delineating the response of cytoplasmic PRRs in the newborn to pathogen-associated molecular patterns (PAMPs) typical of intracellular pathogens represents a vital first step towards identifying strategies aimed to ameliorate the newborn’s greater susceptibility to intracellular pathogens. We, therefore, stimulated adult and cord blood with PAMPs typical of cytoplasmic pathogens and followed cytokine production both globally (secreted into the culture supernatant) as well as on the cellular level (intracellular cytokine cytometry (ICC)). We were surprised to find that neonatal blood secreted significantly more IFNα, IP-10, IL-8 and MCP-1 compared to adult blood, especially following stimulation of the PRR Stimulator of Interferon genes (STING). However, we were unable to detect any response to these PAMPs using ICC; this likely stems from the requirement of positive cytokine feedback mechanism necessary for production of type 1 interferons that was inhibited in our ICC set-up. Our data, taken together with the emergence of STING as a key PRR in the detection of intracellular pathogens, e.g. Listeria and several viruses, led us to hypothesize that altered response to STING may be functionally related to the known exquisite sensitivity of newborns to infection with such pathogens. Additional studies aimed at identifying the biological role of activation of cytoplasmic pattern recognition receptors will be conducted to understand the age-related differential immune response to intracellular infections.
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