IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

Lei, Jun; Vermillion, Meghan S.; Jia, Bei; Xie, Han; Xie, Li; McLane, Michael; Sheffield, Jeanne S.; Pekosz, Andrew; Brown, Amanda; Klein, Sabra L.; Burd, Irina

doi:10.1172/jci.insight.122678

Cited by 35 publications

(58 citation statements)

References 94 publications

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“…Thus, Peli1 may directly induce cell death or indirectly by mediating the inflammatory cytokine responses in trophoblasts and hNSCs upon ZIKV infection. Furthermore, it was reported that increased levels of placental type I IFNs cause abnormal architecture of the maternal-fetal barrier [45,46]. We also noted that fetal tissues collected from Peli1 -/dams on E13.5 showed lower viral loads following a high dose of ZIKV infection at E6.5.…”

Section: Plos Pathogenssupporting

confidence: 53%

“…ZIKV-induced inflammatory immune responses in human cerebral organoids were accompanied either by the depletion of hNS/PCs, or alterations in neuronal differentiation among human NS/PCs [44]. Elevated levels of placental type I IFNs and IL-1β were reported to promote fetal demise upon congenital ZIKV infection [45,46]. Despite the evidence of inflammation in induction of CZS, the underlying immune mechanisms are not clearly understood.…”

Section: Plos Pathogensmentioning

confidence: 99%

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Peli1 signaling blockade attenuates congenital zika syndrome

Luo

Wang

et al. 2020

PLoS Pathog

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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.

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Section: Plos Pathogenssupporting

confidence: 53%

Section: Plos Pathogensmentioning

confidence: 99%

Peli1 signaling blockade attenuates congenital zika syndrome

Luo

Wang

et al. 2020

PLoS Pathog

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“…Furthermore, this inflammatory response induces passage of cytokines and chemokines to the fetal brain, generating local immune response and further activation of the immune system of the fetus 34,35,71 . Of all the cytokines implicated, IL‐1β stands out, as the main mediator of perinatal brain injury and it directly and indirectly induces neurotoxicity, 23,72 whereas its blockage using pharmacological and genetic methods exerts neuroprotective effects in animal studies 9,48,73‐75 …”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy

Chudnovets

Lei

et al. 2020

American J Rep Immunol

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Problem Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL‐1β is a key inflammatory regulator of adverse pregnancy outcomes. Method of study Pregnant mice were treated with intraperitoneal injections of IL‐1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL‐1β signaling markers. Results As compared with non‐treated dams, maternal injections with IL‐1β resulted in increased p‐NF‐κB and caspase‐1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL‐1β production. These findings were confirmed by increased levels of IL‐1β in the placentas of the IL‐1β‐treated dams. Systemic treatment of dams with IL‐1β suppressed Stat1 signaling. Maternal inflammation caused by IL‐1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1 μg of IL‐1β, respectively. In the placentas, there was an IL‐1β dose‐dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL‐1β dose‐dependent reduction in cortical neuronal morphology. Conclusion This work demonstrates that systemic IL‐1β injection causes dose‐dependent structural and functional changes in the placenta and fetal brain.

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“…Mouse models and epidemiologic data have shown that inflammatory immune responses generated by viral infection during pregnancy can result in negative effects on fetal brain development. [26][27][28] During the H1N1 pandemic, infected women had higher rates of preterm birth. 29 Therefore, although placental transmission of the virus may not occur with SARS-CoV-2 infection, other short-and long-term effects from inflammation may adversely affect the developing fetus.…”

Section: Immune Responses To Covid-19mentioning

confidence: 99%

SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review

Narang

Enninga

Gunaratne

et al. 2020

Mayo Clinic Proceedings

245

210

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The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has been associated with worse outcomes in several patient populations, including the elderly and those with chronic comorbidities. Data from previous pandemics and seasonal influenza suggest that pregnant women may be at increased risk for infectionassociated morbidity and mortality. Physiologic changes in normal pregnancy and metabolic and vascular changes in high-risk pregnancies may affect the pathogenesis or exacerbate the clinical presentation of COVID-19. Specifically, SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) receptor, which is upregulated in normal pregnancy. Upregulation of ACE2 mediates conversion of angiotensin II (vasoconstrictor) to angiotensin-(1-7) (vasodilator) and contributes to relatively low blood pressures, despite upregulation of other components of the reninangiotensin-aldosterone system. As a result of higher ACE2 expression, pregnant women may be at elevated risk for complications from SARS-CoV-2 infection. Upon binding to ACE2, SARS-CoV-2 causes its downregulation, thus lowering angiotensin-(1-7) levels, which can mimic/worsen the vasoconstriction, inflammation, and pro-coagulopathic effects that occur in preeclampsia. Indeed, early reports suggest that, among other adverse outcomes, preeclampsia may be more common in pregnant women with COVID-19. Medical therapy, during pregnancy and breastfeeding, relies on medications with proven safety, but safety data are often missing for medications in the early stages of clinical trials. We summarize guidelines for medical/obstetric care and outline future directions for optimization of treatment and preventive strategies for pregnant patients with COVID-19 with the understanding that relevant data are limited and rapidly changing.

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IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection

Cited by 35 publications

References 94 publications

Peli1 signaling blockade attenuates congenital zika syndrome

Peli1 signaling blockade attenuates congenital zika syndrome

Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy

SARS-CoV-2 Infection and COVID-19 During Pregnancy: A Multidisciplinary Review

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