Dysregulated Metabolism Underpins Zika Virus Infection-Associated Impairment in Fetal Development

Yau, Clement; Low, John Z.H.; Gan, Esther S.; Kwek, Swee Sen; Liang, Cui; Tan, Hwee-Cheng; Mok, Darren Z L; Chan, Chee-Yong; Sessions, October M.; Watanabe, Sumio; Vasudevan, Subhash G.; Lee, Yie Hou; Rong, Chan; Ooi, Eng Eong

doi:10.2139/ssrn.3890378

Cited by 4 publications

(8 citation statements)

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“…Increased glucose consumption during ZIKV replication has previously been seen using a diversity of human and non-human cell lines (29)(30)(31)(32). Increased glycose consumption was reflected by cytosolic processing of glucose and elevated lactate release during infection, as observed by others (21,30,31). Higher activation of glycolysis in late hi-NPCs, the subtype with lower baseline consumption rate of glucose, may suggest that ZIKV requires increased by-products of glycolysis to support additional processes such as redox clearance and nucleotide production (21), and/or to signal cell survival-related pathways necessary for efficient viral replication (33,34).…”

Section: Discussionmentioning

confidence: 94%

“…Results from human monocytes and drosophila suggest ZIKV infection increases beta-oxidation of fatty acids at early time-points(37,38). However, results obtained from mouse models of ZIKV pathology showing decreases in the TCA cycle, oxidative phosphorylation, and cytosolic levels of NAD + (30,33) may suggest a decreased beta-oxidation of fatty acids. We showed that ZIKV simultaneously increases the expression of genes involved in fatty acid beta-oxidation and biosynthesis yet to different rates between neuronal progenitor subtypes.…”

Section: Discussionmentioning

confidence: 99%

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Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Gilbert‐Jaramillo

Purnama

Molnár

et al. 2022

Preprint

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Neuronal progenitor subtypes have distinct fate restrictions regulated by time-dependent activation of energetic pathways during development. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that 2D in vitro differentiation of human induced pluripotent stem cells into cortical neuronal progenitors (hi-NPCs) produces metabolically distinct populations that resemble the metabolic profile of forebrain progenitor subtypes. These progenitor subtypes showed differential replication rates of neurotropic ZIKV. This differential replication alters the transcription of metabolic genes and upregulates the glycolytic capacity of progenitor subtypes. Analysis using Imagestream revealed subtype-specific metabolic alterations at different stages during ZIKV replication. During early stages of infection, ZIKV replication in early progenitors increases lipid droplet abundance and decreases mitochondrial size and membrane potential. During later stages infection, early progenitors show increased subcellular distribution of lipid droplets, whilst late progenitors show decreased mitochondria size. The finding that there are hi-NPC subtype-specific alterations of cellular metabolism during ZIKV infection provide a platform to investigate the mechanisms on how ZIKV differentially dysregulate the metabolism of forebrain progenitor subtypes which may help explain the differences in brain damage over each trimester.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Gilbert‐Jaramillo

Purnama

Molnár

et al. 2022

Preprint

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“…Recently, ZBP1/RIPK1/RIPK3 was shown to induce a subset of ISGs in cortical neurons during ZIKA virus infection (Daniels et al, 2019). ZIKA virus induces mitochondrial damage (Ledur et al, 2020; Yau et al, 2021), and the closely related Dengue flavivirus can trigger mtDNA release and promote cGAS-STING signaling (Aguirre et al, 2017; Sun et al, 2017). Therefore, it is possible that RIPK1 and/or RIPK3 participate in the ZBP1-cGAS complex and help sustain IFN-I signaling and ISG expression downstream of mitochondrial stress.…”

Section: Discussionmentioning

confidence: 99%

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Lei

VanPortfliet

Chen

et al. 2022

Preprint

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Mitochondrial DNA (mtDNA) is a potent agonist of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING)-type I interferon (IFN-I) pathway. However, the kinetics of mtDNA detection by cGAS or other nucleic acid sensors and the exact immunostimulatory features of mtDNA remain poorly defined. Here, we show that robust and sustained IFN-I responses downstream of mtDNA stress require the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) in a cell death independent manner. Cells experiencing persistent mtDNA release display robust ZBP1 expression, as well as a marked increase in the cytoplasmic pool of cGAS. Biochemical and microscopy analyses reveal that the receptor-interacting protein homotypic interaction motif (RHIMs) of ZBP1 bind the N-terminus of cGAS, leading to its entrapment in the cytoplasm. Moreover, we show that genetic and pharmacologic induction of mtDNA stress leads to the mitochondrial and cytoplasmic accumulation of Z-form DNA. Nuclease treatment or deletion of Z-DNA binding domains of ZBP1 reduces its interaction with cGAS and impairs cGAMP production downstream of mtDNA stress. Finally, we uncover that ZBP1 is a novel regulator of IFN-I-mediated disease pathology, working in tandem with the cGAS-STING pathway to sense mtDNA instability and sustain IFN-I signaling that contributes to cardiac remodeling and heart failure. These results provide new insight into the molecular mechanisms of mtDNA sensing by the innate immune system and reveal that ZBP1 is a cooperative partner for cGAS. Moreover, our findings highlight ZBP1 as a potential therapeutic target in heart failure and other disorders where mtDNA instability drives disease-promoting IFN-I and inflammatory responses.

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“…Infection of these neuronal tissues is associated with direct tissue damage through the cytopathic effect (23)(24)(25), molecular level pathogenesis (26), disruption of cell division (23,(27)(28)(29), and dysregulation of developmental pathways (30)(31)(32)(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

“…Upon fetal infection, ZIKV also breaches the blood-brain barrier and infects susceptible neuronal tissue (19)(20)(21)(22)(23). Infection of these neuronal tissues is associated with direct tissue damage through the cytopathic effect (24)(25)(26), molecular level pathogenesis (27), disruption of cell division (24,(28)(29)(30), and dysregulation of developmental pathways (31)(32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

Zika virus NS4A hijacks host ANKLE2 to promote viral replication

Fishburn

Hoang

Lopez

et al. 2022

Preprint

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Zika virus (ZIKV) is infamous among flaviviruses for its unique association with congenital birth defects, notably microcephaly. We previously mapped ZIKV-host protein interactions and identified the interaction between ZIKV NS4A and host ANKLE2, which itself has established ties to congenital microcephaly. In fruit flies, NS4A induces microcephaly phenotypes in an ANKLE2-dependent manner. This suggests that NS4A interacts with ANKLE2 to dysregulate cell behavior and contributes to abnormal host neurodevelopment. Here, we explore the role of ANKLE2 in ZIKV replication to understand the biological significance of the interaction from the viral perspective. We show that knockdown of ANKLE2 reduces replication of two ZIKV strains, across multiple MOIs. We observe that localization of ANKLE2 is drastically shifted to sites of NS4A and viral replication. We investigate which domains of ANKLE2 mediate this behavior and the interaction with NS4A. Using co-immunoprecipitation, we show that deletion of either the transmembrane or LEM domain has little impact on the interaction, but deletion of both significantly reduces interaction with NS4A. Finally, we show that the C-terminal transmembrane domains of NS4A stabilize the interaction with ANKLE2. Together, these results suggest NS4A interacts with ANKLE2 through a combination of its transmembrane and LEM domains, bringing it to sites of ZIKV replication to promote replication through an unknown mechanism. Taken together with our previous results, our findings indicate that, in the process of hijacking ANKLE2 for replication, ZIKV disrupts its physiological function to cause disease.

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Dysregulated Metabolism Underpins Zika Virus Infection-Associated Impairment in Fetal Development

Cited by 4 publications

References 0 publications

Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Zika virus NS4A hijacks host ANKLE2 to promote viral replication

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