Stemming the tide of viral infection

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Science Immunology  02 Mar 2018:
Vol. 3, Issue 21, eaat3914
DOI: 10.1126/sciimmunol.aat3914


A subset of canonical “interferon-stimulated” antiviral genes are intrinsically expressed in and protect mammalian stem cells.

Interferon-pathway activation is a primary feature of the innate immune response to viral infection. Although this paradigm holds true for most cell types, several groups have previously made the observation that stem cell populations are largely refractory to stimulation by traditional interferon-pathway agonists. Interestingly, stem cell populations have also been found to be relatively resistant to viral infection. This apparent paradox has led to the hypothesis that the mechanism of antiviral defense in stem cells is not dependent on canonical interferon pathway activation. Current evidence in support of this hypothesis derives largely from prior work proposing that mammalian stem cells may use an RNA interference–based antiviral mechanism akin to that used by plants and insects.

A new study by Wu and colleagues demonstrates an additional mechanism of antiviral defense in mammalian stem cells that is based on the cell-autonomous expression of a subset of canonical “interferon-stimulated” antiviral genes (e.g., IFITM genes), which are expressed even in the absence of any exogenous interferon-signaling. The authors show that these genes are expressed spontaneously in pluripotent and multipotent mammalian stem cell populations, are down-regulated upon terminal differentiation, and are not coexpressed with other interferon-associated genes with antiproliferative or proapoptotic function. In addition, the authors show that high expression of these antiviral genes in stem cell populations correlates with their relative resistance to infection with multiple viruses. Using CRISPR (clustered regularly interspaced short palindromic repeats)/CAS9 (CRISPR-associated protein 9) and short hairpin RNA-mediated functional experiments the authors also demonstrate that IFITM genes are critical mediators of the in vitro and in vivo susceptibility of stem cell populations to viral infection.

The cell-autonomous expression of antiviral genes by stem cell populations raises several interesting biological questions. Namely, what is the mechanism of spontaneous antiviral gene expression in stem cells? If not due to activation by exogenous interferon-pathway agonists, might it reflect activation of innate viral-sensing pathways by endogenous ligands (e.g., endogenous retroviruses) that would lead to cell-intrinsic activation of interferon pathways? If so, how are stem cells able to achieve selective up-regulation of antiviral genes and avoid the antiproliferative and proapoptotic effects of interferon-pathway activation? These questions were not definitively answered in the present study but represent interesting avenues for further investigation.

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