Peli1 signaling blockade attenuates congenital zika syndrome

Abstract

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.

Dendritic Cell–Specific Role for Pellino2 as a Mediator of TLR9 Signaling Pathway

“…Although roles for Pellino1 and Pellino3 in TLR9 signaling have not been described, they are involved in regulating RNA recognition via TLR3 or during antiviral responses. Pellino1 regulates antiviral immune responses to multiple RNA viruses such as West Nile virus ( 62 ), Zika virus ( 63 ), rhinovirus ( 64 ), and vascular stomatitis virus ( 56 ), whereas we have previously delineated a role for Pellino3 in response to encephalomyocarditis virus ( 29 ). Pellino1 has been shown to regulate IFN-β production in macrophages and microglia ( 25 , 56 ), whereas Pellino3 controls type I IFNs in macrophages and DCs following TLR3 activation ( 29 ).…”

The roles of microglia in viral encephalitis: from sensome to therapeutic targeting

“…Recently, the Peli1 protein, which is an E3 ubiquitin ligase, has been implicated in promoting viral replication and inflammation in the CNS in mouse models of VSV and WNV encephalitis and in a mouse model of congenital Zika syndrome. 80 , 83 , 84 In a mouse model of congenital Zika syndrome, Peli1 promotes inflammation by mediating NF-κB activation and the expression of IL-1β, TNF-α, and IL-6. Blocking Peli1 attenuated congenital malformations in mice, 84 confirming a proinflammatory role in this model.…”

“… 80 , 83 , 84 In a mouse model of congenital Zika syndrome, Peli1 promotes inflammation by mediating NF-κB activation and the expression of IL-1β, TNF-α, and IL-6. Blocking Peli1 attenuated congenital malformations in mice, 84 confirming a proinflammatory role in this model. Mice that do not express Peli1 showed reduced viral titers in the CNS and had increased survival upon a lethal VSV or WNV encephalitis challenge compared to WT mice.…”

The Emerging Roles of Pellino Family in Pattern Recognition Receptor Signaling

“…IRF3 and IRF7 are the most important transcription factors regulating type I IFN expression (80). Pellino1 possesses a novel function in human viral pathogen infection (41,62,84,85) depending on TRIF. Pellino1, as a TLR3 positive regulator (18,37,86), is involved in modulating the production of proinflammatory cytokines (37,86) and induction of IFN-I in the TLR3 pathway (41,44,86,87).…”