Innate antiviral immunity of human embryonic stem cells
Dr S Macias
Dr P De Sousa
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
Unlike differentiated or somatic cells, embryonic stem cells (ESCs) are unable to activate their complete innate immune response when confronted with pathogens such as viruses.
When cells sense the presence of a viral infection, they induce the expression of type-I Interferons (IFNs) as part of the innate immune response. Type-I IFNs are secreted cytokines that activate the antiviral response in both the infected and neighbouring cells. However, this response is naturally absent in mammalian pluripotent stem cells and also oocytes.
In their natural setting, the inner cell mass cells from where ESCs originate are assumed to be protected from viral infections by the trophoblast, which forms the outer layer of the pre-implantation blastocyst. In addition, ESCs can mildly respond to exogenous IFN, which suggests that could activate an antiviral state if necessary, for instance, when stimulated by maternal IFNs. Recent findings also show that human ESCs (hESCs) constitutively express a subset of Interferon stimulated genes that protect from viruses. All these findings propose a model in which hESCs employ alternative antiviral mechanisms, bypassing the need of the IFN response.
It is still not understood why human ESCs silence IFN production. Our hypothesis is that silencing this response acts as a protective mechanism against aberrant IFN activation by endogenous immunogenic RNAs, such as retrotransposons and retroviruses, which are especially highly expressed during the early stages of embryonic development.
Here, we aim to study how and why hESCs silence IFN expression. For this purpose, we will first genetically manipulate hESCs to enable IFN expression, by overexpressing key components of the antiviral innate immune pathway and second, we will investigate the effects of IFN activation in maintenance of pluripotency and during differentiation.
With this project we aim at describing the reason and mechanism of IFN expression silencing in hESCs and to study the consequences of aberrant IFN activation during this critical developmental stage.
This project will be a collaborative effort between two different research groups. First, the group of Dr. de Sousa will provide the essential knowledge to culture and genetically manipulate human stem cells. The characterization of the innate immune response of human stem cells will be performed in the group of Dr. Macias. Both groups are based at the University of Edinburgh.
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Wu et al. Intrinsic Immunity shapes viral resistance of stem cells. Cell (2018), 172:423-483.e25
Hong XX and Carmichael GG. Innate Immunity in Pluripotent Human Cells. The Journal of Biological Chemistry (2013), 288 (22) 16916-16205
Pells S.C., Koutsouraki E., Morfopoulou S., Valencia-Cadavid S., Malinowski A.R., Riddoch R. Tomlinson S.R., Kalathur R., Futschik M.E., De Sousa P.A. (2015) Identification of novel epigenetically-conserved biomarkers of human embryonic stem cells critical for maintenance of an undifferentiated state. PLOS ONE Jul 7;10(7):e0131102. doi: 10.1371/journal.pone.0131102.
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