Synergistic blockade of cyclophilin A and pathogenic immunity minimizes pregnancy-context pathologies in response to the Zika virus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308795 | GEO | 2026/04/22
REPOSITORIES: GEO
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Project description:Zika virus (ZIKV) infection has caused severe unexpected clinical outcomes in neonates and adults during the recent outbreak in Latin America, particularly in Brazil. Congenital malformations associated with ZIKV have been frequently reported; nevertheless, the mechanism of vertical transmission and the involvement of placental cells remains unclear. In this study, we applied quantitative proteomics analysis in a floating explant model of chorionic villi of human placental tissues incubated with ZIKV and with ZIKV pre-adsorbed with anti-ZIKV envelope protein. The regulation of specific proteins was measured using immunofluorescence and immunoperoxidase assays. Altered levels of proteins were involved in cell proliferation, apoptosis, inflammatory processes, and the integrin-cytoskeleton complex. Antibody-opsonized ZIKV particles differentially modulated the pattern of protein expression in placental cells; this phenomenon may play a pivotal role in determining the course of infection and the role of mixed infections. These data fill gaps in our understanding of ZIKV in the placenta and help identify infection control targets.
2021-12-30 | PXD025764 | Pride
Project description:We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.
2023-06-03 | GSE205631 | GEO
Project description:We and others have demonstrated Zika virus (ZIKV) congenital infection evades double-stranded RNA detection, and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. We used orthogonal approaches to test the hypothesis that ZIKV disrupts placental miRNAs to enable viral persistence and fetal pathogenesis. In primary human trophoblasts, high-throughput sequencing crosslinking and immunoprecipitation (AGO-HITS-CLIP) demonstrated an unexpected disruption of placental miRNA-regulated TGF-β networks. In gnotobiotic mice, absence of microbes rendered normally resistant mice susceptible to congenital ZIKV infection, and placental spatial transcriptomics revealed distinct microenvironments defined by significant upregulation of complement cascade components. Finally, treatment of ZIKV-infected mice with the RNAi-enhancer enoxacin led to loss of ZIKV placental persistence and rescue of fetal growth restriction. These results collectively suggest that ZIKV co-opts miRNA inflammatory regulatory networks to persist in the placenta reservoir, a conduit of vertical transmission and fetal pathogenesis.
2023-06-03 | GSE205609 | GEO
Project description:Zika virus (ZIKV) infection during pregnancy results in an increased risk of spontaneous abortion and vertical transmission across placenta results in severe congenital defects in newborns. While the infectivity and pathological effects of ZIKV on the placental trophoblast progenitor cells in early human embryos remains largely unknown. Here, using the human trophoblast stem cells (hTSCs) isolated from human blastocyst, we showed that hTSCs were permissive to ZIKV infection, while resistance to ZIKV increased with differentiation. Combined CRISPR/Cas9-mediated gene knockout and RNA-seq assays, we demonstrated that the intrinsic expression of AXL and TIM-1, as well as the absence of potent interferon (IFN)-stimulated genes (ISGs), contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived 3 dimensional (3D) placental trophoblast organoid model, we demonstrated that ZIKV infection completely disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Overall, our results clearly demonstrated that hTSCs represented the major target cells of ZIKV, and a possible reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepened our understanding of the characteristics and consequences of ZIKV infection of trophoblast stem cells in early human embryo.
2023-08-03 | GSE229702 | GEO
Project description:African swine fever virus (ASFV) is a large DNA virus that poses a major threat to the global swine industry. Its virion is encapsulated by an icosahedral capsid predominantly composed of the structural protein p72, which constitutes approximately one-third of the total virion mass. Despite its abundance, the mechanisms regulating p72 stability remain poorly understood. Here, we demonstrate that host-mediated stabilization of p72 is essential for efficient ASFV replication. Mass spectrometry of p72 co-precipitates identified host cyclophilin A (CypA, also known as PPIA) as a key binding partner of p72. CypA interacts with p72 both in vitro and in vivo, specifically engaging exposed regions of p72 via its hydrophobic cavity. CypA interaction stabilizes p72 by reducing K63-linked ubiquitination and preventing proteasomal degradation, whereas cyclic CypA inhibitors destabilize p72 by disrupting this interaction and promoting its ubiquitination. Importantly, genetic or pharmacological inhibition of CypA markedly impairs ASFV replication. Mechanistically, CypA inhibition disrupts viral factory formation and virion assembly by decreasing p72 protein accumulation without affecting its transcription. Together, our findings uncover a previously unrecognized host-dependent mechanism regulating capsid protein stability and highlight host CypA as a promising target for antiviral strategies against ASFV.
2026-01-15 | GSE300823 | GEO
Project description:Vertical transmission of Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10480-fold higher expression of viral attachment factors AXL, GAS6 and PROS1 and 3880-fold increase in ZIKV infectiousness/propagation in decidual cells (DCs) versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased while expression of innate immune response genes are significantly decreased in first trimester versus term DCs. ZIKV-infected DC supernatants increased cytotrophoblast infection up to 252-fold compared to directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited ZIKV infection in both cell types. We conclude that decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher ZIKV infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal ZIKV transmission.
2020-03-14 | GSE146980 | GEO
Project description:We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells, and this degradation is via a PROTAC mechanism. These molecules have high specificity for CypA illustrated by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA targeting PROTACs inhibit viral replication potently, and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.
2024-11-29 | PXD057024 | Pride
Project description:The isomerase activity of Cyclophilin A is important for midbody abscission during cell division, however to date, midbody substrates remain unknown. In this study, we report that the GTP-binding protein Septin 2 interacts with Cyclophilin A. We highlight a dynamic series of Septin 2 phenotypes at the midbody, previously undescribed in human cells. Furthermore, Cyclophilin A depletion or loss of isomerase activity is sufficient to induce phenotypic Septin 2 defects at the midbody. Structural and molecular analysis reveals that Septin 2 proline 259 is important for interaction with Cyclophilin A. Moreover, an isomerisation-deficient EGFP-Septin 2 proline 259 mutant displays defective midbody localisation, and undergoes impaired abscission, consistent with data from cells with loss of Cyclophilin A expression or activity. Collectively, this data reveals Septin 2 as a novel interacting partner and isomerase substrate of Cyclophilin A at the midbody that is required for abscission during cytokinesis in cancer cells.
2023-10-24 | PXD042822 | Pride
Project description:Cyclophilin A (CyPA), a member of the family of cyclophilins, is widely expressed by all prokaryotic and eukaryotic cells. Upon activation, CyPA can also be released from platelets, and engages in extracellular functions via interaction with the CD147 receptor that contribute to cardiovascular disease. CyPA was recently found to be acetylated at K82 and K125, two lysines conserved in most species, and these modifications were required for secretion of acetylated CyPA in response to cell activation in vascular smooth muscle cells. We here addressed whether acetylation at these sitesis also required for release of acetylated CyPA from platelets. Western blot analyses demonstrated the presence of CyPA in human and mouse platelets. Thrombin-stimulation resulted in CyPA release from platelets, however, no acetylation was observed –neither in cell lysates nor in supernatants of untreatedand thrombin-activated platelets. Similar results were obtained after immunoprecipitation of CyPA from platelets. In vitro acetylation of recombinant humanCyPA by p300 acetyltransferase likewise did not induce CyPA acetylation. Using shotgun proteomics we detected two CyPA peptide precursors in the recombinant protein, acetylatedat K28, but again no acetylation was found in CyPA from resting or stimulated platelet samples. Our findings suggest that acetylation of CyPA is not a major protein modification in platelets, and that CyPA acetylation at K82 and K125 is not required for its secretion from platelets.
2022-02-22 | PXD027289 | Pride
Project description:Zika Virus (ZIKV) infection has been associated with fetal abnormalities by compromising placental integrity. Flavivirus have shown deregulation of the host proteome, specially extracellular matrix (ECM) proteins. Our hypothesis is that ZIKV infection of placental tissue deregulates specific ECM proteome, allowing a mechanism of persistent infection and loss of placental integrity. Using nine different placental samples from Puerto Rico collected during 2016 ZIKV epidemic, we compared the proteome of five ZIKV infected samples with uninfected controls. Quantitative proteomics was performed using tandem mass tag TMT10plex™ Isobaric Label Reagent Set followed by Q Exactive™ Hybrid Quadrupole Orbitrap Mass Spectrometry. Identification of proteins was performed by Proteome Discover 2.1, and protein fold change in both groups was compared using Limma software. Differentially expressed proteins were analyzed with STRING and Ingenuity Pathway using both the fold change and p-value. TMT analysis showed that ZIKV infected placentas had 94 reviewed differentially abundant proteins, 32 More abundant and 62 Less abundant. STRING analysis results indicate that 45 of the deregulated proteins are cellular components of the ECM and 16 play a role in its structure and organization. Some of the significantly More abundant proteins were Fibrinogen, Vitronectin and Fibronectin. The results we observed in the samples from naturally infected pregnant women may contribute to the understanding of the mechanism (s) employed by ZIKV during placental infection and give insight on novel targets used to disrupt placental function.
2022-06-09 | PXD023964 | Pride