Metabolic reprogramming by Zika virus provokes inflammation in human placenta

Abstract

The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function.

Mitophagy antagonism by Zika virus reveals Ajuba as a regulator of PINK1-Parkin signaling, PKR-dependent inflammation, and viral invasion of tissues

“…As illustrated by infection of primary human fibroblasts, once this signaling is initiated, even a reduction in virus titer through inhibition of the ISR was not sufficient to suppress chemokine expression. Evidence for these processes in humans has been observed in placental tissues from ZIKV-infected mothers including mitochondrial dysfunction, metabolic alterations and induction of inflammatory mediators (Chen et al, 2020). The current work identifies a molecular mechanism for these observations encoded through ZIKV NS5 to amplify mitochondrial stress responses in infected tissue (Supplementary Figure 6).…”

“…Importantly, E.coli-expressed PINK1 has low autophosphorylation activity (Rasool et al, 2018), but auto-phosphorylation of PINK1 at Thr257 significantly increased when PINK1 was incubated with increasing levels of Ajuba ( Figure 3D,E). Ajuba can be phosphorylated by the kinase with which it interacts (Chen et al, 2016) prompting us to test if PINK1 phosphorylates Ajuba following coexpression by IP and mass-spectrometry. Based on the PINK1 phosphorylation consensus sequence (Torii et al, 2020), two residues in the pre-LIM domain of Ajuba are predicted to be phosphorylated by PINK1, S39 and S136.…”

“…Ajuba belongs to the LIM family of proteins whose demonstrated functions include the relief of Ser/Thr kinase autoinhibition and as scaffolding adaptor proteins to promote association of multi-protein complexes (Jia et al, 2020). Ajuba has been identified as an activator of mitotic kinases, including Aurora-A and CDK1 (Chen et al, 2016;Hirota et al, 2003), that also have central functions in mitochondrial dynamics (Archer, 2013). Our results demonstrate that Ajuba is recruited to mitochondria following various inducers of mitochondrial stress including MAVS activation where it is required for efficient activation of PINK1.…”

Quo vadis? Central Rules of Pathogen and Disease Tropism

“…Co-culture of neurons with T. cruzi and IFNγ-activated macrophages led to neuronal death, which was abrogated by inhibitors of nitric oxide production ( Almeida-Leite et al., 2007 ). Zika virus increases lipid droplet levels not only in infected cells but also in adjacent uninfected cells ( Chen et al., 2020 ). Many pathogens also lead to immune cell exhaustion.…”

Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy

“…There remains much to be elucidated in terms of ZIKV infection in human pregnancy. New studies are identifying metabolic reprogramming pathways underpinning innate immune responses to ZIKV which opens additional avenues of investigation ( 157 ) . We refer readers to recent reviews highlighting ZIKV-immune interactions in adverse pregnancy outcomes ( 119 ) and ADE ( 158 ).…”