scholarly journals Apoptosis During ZIKA Virus Infection: Too Soon or Too Late?

2021 ◽  
Author(s):  
Jonathan Turpin ◽  
Daed El Safadi ◽  
Grégorie Lebeau ◽  
Morgane Krejbich ◽  
Camille Chatelain ◽  
...  
Keyword(s):  
Cell Death ◽  
Zika Virus ◽  
Cellular Response ◽  
Defense Mechanism ◽  
Cell Types ◽  
Interferon Response ◽  
Control Mechanisms ◽  
Sexually Transmitted ◽  
Antiviral Responses ◽  
Viral Determinants

Cell death by apoptosis is a major cellular response, in the control of tissue homeostasis and as a defense mechanism in case of cellular aggression like an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants, through different pathways, as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans which has caused severe neurological forms, birth defects and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

scholarly journals Evasion of Innate and Intrinsic Antiviral Pathways by the Zika Virus

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 970 ◽  
Author(s):  
Taryn M. Serman ◽  
Michaela U. Gack
Keyword(s):  
Zika Virus ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Granule Formation ◽  
Human Host ◽  
Antiviral Responses ◽  
Innate Immune Signaling ◽  
Nonsense Mediated Mrna Decay

The Zika virus (ZIKV) is a recently emerged mosquito-borne flavivirus that, while typically asymptomatic, can cause neurological symptoms in adults and birth defects in babies born to infected mothers. The interactions of ZIKV with many different pathways in the human host ultimately determine successful virus replication and ZIKV-induced pathogenesis; however, the molecular mechanisms of such host-ZIKV interactions have just begun to be elucidated. Here, we summarize the recent advances that defined the mechanisms by which ZIKV antagonizes antiviral innate immune signaling pathways, with a particular focus on evasion of the type I interferon response in the human host. Furthermore, we describe emerging evidence that indicated the contribution of several cell-intrinsic mechanisms to an effective restriction of ZIKV infection, such as nonsense-mediated mRNA decay, stress granule formation, and “reticulophagy”, a type of selective autophagy. Finally, we summarize the recent work that identified strategies by which ZIKV modulated these intrinsic antiviral responses.

scholarly journals Concomitant Pyroptotic and Apoptotic Cell Death Triggered in Monocytes Infected by Zika Virus

2021 ◽  
Author(s):  
Chunxia Wen ◽  
Yufeng Yu ◽  
Chengfeng Gao ◽  
Xian Qi ◽  
Carol J. Cardona ◽  
...  
Keyword(s):  
Cell Death ◽  
Zika Virus ◽  
Apoptotic Cell ◽  
Cell Types ◽  
Viral Pathogenesis ◽  
Productive Infection ◽  
Host Responses ◽  
Monocytic Cells ◽  
Caspase 1 ◽  
Canonical Approach

ABSTRACTZika virus (ZIKV) is a positive-sense RNA flavivirus and can cause serious neurological disorders including microcephaly in infected fetus. As a mosquito-borne arbovirus, ZIKV enters bloodstream and is transmitted into the fetus through the placenta in pregnant women. Monocytes are considered one of the earliest blood cell types to be infected by ZIKV. As a first line defence, monocytes are crucial components in innate immunity and host responses and may impact viral pathogenesis in humans. Previous studies have shown that ZIKV infection can activate inflammasomes and induce proinflammatory cytokines in monocytes. In this report, we showed that ZIKV carried out a productive infection, which lead to cell death in human and murine monocytic cells. In addition to the presence of cleaved caspase-3, indicating that apoptosis was involved, we identified the cleaved caspase-1 and gasdemin D (GSDMD) as well as increased secretion of IL-1β and IL-18, suggesting that the inflammasome was activated that may lead to pyroptosis in infected monocytes. The pyroptosis was NLRP3-dependent and could be suppressed in the monocytes treated with shRNA to target and knockdown caspase-1, or an inhibited for caspase-1, indicating that the pyroptosis was triggered via a canonical approach. Our findings in this study demonstrate a concomitant occurrence of apoptosis and pyroptosis in ZIKV-infected monocytes, with multiple mechanisms involved in the cell death, which may have potentially significant impacts on viral pathogenesis in humans.

scholarly journals Fibroblast Growth Factor 2 Enhances Zika Virus Infection in Human Fetal Brain

2019 ◽  
Vol 220 (8) ◽  
pp. 1377-1387 ◽  
Author(s):  
Daniel Limonta ◽  
Juan Jovel ◽  
Anil Kumar ◽  
Julia Lu ◽  
Shangmei Hou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Zika Virus ◽  
Cellular Response ◽  
Fetal Brain ◽  
Fibroblast Growth Factor 2 ◽  
Interferon Response ◽  
Fibroblast Growth ◽  
Human Fetal Brain ◽  
Zikv Infection

Abstract Zika virus (ZIKV) is an emerging pathogen that can cause microcephaly and other neurological defects in developing fetuses. The cellular response to ZIKV in the fetal brain is not well understood. Here, we show that ZIKV infection of human fetal astrocytes (HFAs), the most abundant cell type in the brain, results in elevated expression and secretion of fibroblast growth factor 2 (FGF2). This cytokine was shown to enhance replication and spread of ZIKV in HFAs and human fetal brain explants. The proviral effect of FGF2 is likely mediated in part by suppression of the interferon response, which would represent a novel mechanism by which viruses antagonize host antiviral defenses. We posit that FGF2-enhanced virus replication in the fetal brain contributes to the neurodevelopmental disorders associated with in utero ZIKV infection. As such, targeting FGF2-dependent signaling should be explored further as a strategy to limit replication of ZIKV.

scholarly journals Epididymal epithelium propels early sexual transmission of Zika virus in the absence of interferon signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexander G. Pletnev ◽  
Olga A. Maximova ◽  
Guangping Liu ◽  
Heather Kenney ◽  
Bianca M. Nagata ◽  
...  
Keyword(s):  
Zika Virus ◽  
Equal Opportunity ◽  
Vas Deferens ◽  
Sexual Transmission ◽  
Interferon Signaling ◽  
Sexually Transmitted ◽  
Antiviral Responses ◽  
Productive Phase ◽  
Male To Female ◽  
Different Parts

AbstractRecognition of Zika virus (ZIKV) sexual transmission (ST) among humans challenges our understanding of the maintenance of mosquito-borne viruses in nature. Here we dissected the relative contributions of the components of male reproductive system (MRS) during early male-to-female ZIKV transmission by utilizing mice with altered antiviral responses, in which ZIKV is provided an equal opportunity to be seeded in the MRS tissues. Using microRNA-targeted ZIKV clones engineered to abolish viral infectivity to different parts of the MRS or a library of ZIKV genomes with unique molecular identifiers, we pinpoint epithelial cells of the epididymis (rather than cells of the testis, vas deferens, prostate, or seminal vesicles) as a most likely source of the sexually transmitted ZIKV genomes during the early (most productive) phase of ZIKV shedding into the semen. Incorporation of this mechanistic knowledge into the development of a live-attenuated ZIKV vaccine restricts its ST potential.

scholarly journals Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2

2015 ◽  
Vol 83 (9) ◽  
pp. 3410-3417 ◽  
Author(s):  
Kathleen Nudel ◽  
Paola Massari ◽  
Caroline A. Genco
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Cell Types ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Cell Death Pathways ◽  
Host Cell Death ◽  
Cervical Epithelial Cells

Several bacterial pathogens persist and survive in the host by modulating host cell death pathways. We previously demonstrated thatNeisseria gonorrhoeae, a Gram-negative pathogen responsible for the sexually transmitted infection gonorrhea, protects against exogenous induction of apoptosis in human cervical epithelial cells. However, induction of cell death byN. gonorrhoeaehas also been reported in other cell types. The mechanisms by whichN. gonorrhoeaemodulates cell death are not clear, although a role for the inhibitor of apoptosis-2 (cIAP2) has been proposed. In this study, we confirmed thatN. gonorrhoeaeinduces production of cIAP2 in human cervical epithelial cells. High levels of intracellular cIAP2 were detected early afterN. gonorrhoeaestimulation, which was followed by a marked decrease at 24 h. At this time point, we observed increased levels of extracellular cIAP2 associated with exosomes and an overall increase in production of exosomes. Inhibition of cIAP2 inN. gonorrhoeae-stimulated epithelial cells resulted in increased cell death and interleukin-1β (IL-1β) production. Collectively these results indicate thatN. gonorrhoeaestimulation of human endocervical epithelial cells induces the release of cIAP2, an essential regulator of cell death and immune signaling.

The P-MAPA immunomodulator partially prevents apoptosis induced by Zika virus infection in THP-1 cells

2020 ◽  
Vol 21 ◽  
Author(s):  
Morganna C. Lima ◽  
Elisa A. N. Azevedo ◽  
Clarice N. L. de Morais ◽  
Larissa I. O. de Sousa ◽  
Bruno M. Carvalho ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Virus Infection ◽  
Virus Replication ◽  
Zika Virus ◽  
Mammalian Cells ◽  
Caspase 3 ◽  
Neurological Complications ◽  
Zika Virus Infection

Background: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. Objective: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. Methods: THP-1 cells were subjected at Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, the virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. Results: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. Conclusions: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibits the effects of Zika virus infection in mammalian cells.

scholarly journals Infection, dissemination, and transmission efficiencies of Zika virus in Aedes aegypti after serial passage in mosquito or mammalian cell lines or alternating passage in both cell types

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lourdes G. Talavera-Aguilar ◽  
Reyes A. Murrieta ◽  
Sungmin Kiem ◽  
Rosa C. Cetina-Trejo ◽  
Carlos M. Baak-Baak ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Cell Lines ◽  
Zika Virus ◽  
Cell Types ◽  
Mosquito Cell ◽  
Cell Passage ◽  
Genetic Changes ◽  
Synonymous Substitutions ◽  
Vertebrate Cell

Abstract Background Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) with an urban transmission cycle that primarily involves humans and Aedes aegypti. Evidence suggests that the evolution of some arboviruses is constrained by their dependency on alternating between disparate (vertebrate and invertebrate) hosts. The goals of this study are to compare the genetic changes that occur in ZIKV after serial passaging in mosquito or vertebrate cell lines or alternate passaging in both cell types and to compare the replication, dissemination, and transmission efficiencies of the cell culture-derived viruses in Ae. aegypti. Methods An isolate of ZIKV originally acquired from a febrile patient in Yucatan, Mexico, was serially passaged six times in African green monkey kidney (Vero) cells or Aedes albopictus (C6/36) cells or both cell types by alternating passage. A colony of Ae. aegypti from Yucatan was established, and mosquitoes were challenged with the cell-adapted viruses. Midguts, Malpighian tubules, ovaries, salivary glands, wings/legs and saliva were collected at various times after challenge and tested for evidence of virus infection. Results Genome sequencing revealed the presence of two non-synonymous substitutions in the premembrane and NS1 regions of the mosquito cell-adapted virus and two non-synonymous substitutions in the capsid and NS2A regions of both the vertebrate cell-adapted and alternate-passaged viruses. Additional genetic changes were identified by intrahost variant frequency analysis. Virus maintained by continuous C6/36 cell passage was significantly more infectious in Ae. aegypti than viruses maintained by alternating passage and consecutive Vero cell passage. Conclusions Mosquito cell-adapted ZIKV displayed greater in vivo fitness in Ae. aegypti compared to the other viruses, indicating that obligate cycling between disparate hosts carries a fitness cost. These data increase our understanding of the factors that drive ZIKV adaptation and evolution and underscore the important need to consider the in vivo passage histories of flaviviruses to be evaluated in vector competence studies. Graphic abstract "Image missing"

scholarly journals Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 91
Author(s):  
Verena Schultz ◽  
Stephanie L. Cumberworth ◽  
Quan Gu ◽  
Natasha Johnson ◽  
Claire L. Donald ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Development ◽  
Zika Virus ◽  
Developmental Stages ◽  
Cell Types ◽  
Neural Cells ◽  
Zikv Infection ◽  
Axonal Pathology ◽  
Time Frames

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

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