Interleukin-27 is antiviral at the maternal-fetal interface
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Abstract
Congenital viral infections can have severe consequences for pregnancy and fetal outcomes. Remarkably, the fetal-derived placenta serves as a robust barrier to infection through meticulous regulation by immune effectors and a diverse repertoire of cytokines. Yet, the regulatory roles of many cytokines remain undefined at the maternal-fetal interface. Interleukin 27 (IL-27) is a highly expressed cytokine in the placenta whose functional consequence during congenital infection is unknown. Here, we utilized trophoblast organoids (TO) derived from primary human placentas and a mouse model of congenital viral infection to uncover the functional role of IL-27 signaling during pregnancy. We show that TOs constitutively express IL-27 and its receptor, IL27RA, and demonstrate that IL-27 signaling restricts Zika virus (ZIKV) infection of TOs. Through bulk RNA-sequencing of TOs in the absence and presence of IL-27 signaling, we demonstrate IL-27-mediated upregulation of antiviral genes. Finally, we show that IL-27 signaling is critical within the context of congenital murine ZIKV infection, as IL-27 restricts placental ZIKV burdens and protects against pathologic fetal outcomes early in gestation. These findings collectively demonstrate a novel role for IL-27 in the placenta and establish IL-27 as an innate antiviral defense at the maternal-fetal interface during congenital viral infection.
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protective roles in the context of other viral and microbial infections
could you expand here on what we know about the protective role of IL-27 in those contexts? What do we know about the mechanism of protection and would you predict that it is similar or different to what you observe in the placenta?
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s (IFIT1, DTX3L, PARP9, PARP14, PSME1;
Are there certain immune cell types that are enriched in or that are particularly important in trophoblasts? What do we know about the regulation/role of these genes in those cell types? Does the set of genes upregulated in IL27 stimulated TOs give you any mechanistic insight into what's happening? It would be really helpful to provide more context here around the interplay of these different factors
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d that neutralization of IL-27 or IFNλ led to similar increases in
Could you comment here on how/if IL-27 regulates ifn gamma and where IL-27 sits in relation to ifn gamma in immune pathways? Specifically, how would neutralizing IL-27 be expected to impact ifn gamma reponses?
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