Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

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Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

Scientific Reports ◽

10.1038/s41598-018-25205-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 31

Author(s):

Maxim Seferovic ◽

Claudia Sánchez-San Martín ◽

Suzette D. Tardif ◽

Julienne Rutherford ◽

Eumenia C. C. Castro ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Fetal Loss ◽

Common Marmoset ◽

Zika Virus Infection ◽

Neurodevelopmental Abnormalities

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Experimental Zika Virus Infection in a New World Monkey Model Reproduces Key Features of the Human Disease

10.1101/102145 ◽

2017 ◽

Author(s):

Charles Chiu ◽

Jerome Bouquet ◽

Tony Li ◽

Shigeo Yagi ◽

Claudia Sanchez San Martin ◽

...

Keyword(s):

Zika Virus ◽

Human Disease ◽

New World ◽

World Monkey ◽

Body Fluids ◽

Type I ◽

Interferon Signaling ◽

New World Monkey ◽

Monkey Model ◽

Key Features

ABSTRACTHuman infections by Zika virus (ZIKV), a mosquito-borne flavivirus, are associated with a current widespread outbreak in the Americas, and have been associated with neurological complications and adverse fetal outcomes such as microcephaly in pregnant women. A suitable non-human primate model is urgently needed. To evaluate ZIKV infectivity, pathogenesis, and persistence, we inoculated 4 marmosets with ZIKV and followed them by clinical monitoring and serial sampling of body fluids for up to 11 weeks. We found that marmosets experimentally infected with ZIKV reproduced key features of the human disease, including (1) asymptomatic infection, (2) brief period of detectable virus in serum (<1 week), (3) detection in other body fluids (urine, saliva, semen, and stool) for at least 2 weeks following acute infection, and (4) persistence in lymph nodes, but not other tissues, at 1 month post-infection. ZIKV-positive saliva and serum samples, but not urine, were found to be infectious in cell culture. By day 6 post-inoculation, most marmosets exhibited detectable neutralizing antibody responses concurrent with activation of NK cell and B cell subsets and an increase in circulating cytokines associated with type II interferon signaling, Transcriptome profiling revealed enrichment of immune responses to active viral infection, with up-regulation of both type I and II interferon signaling pathways, anduncovered potential host biomarkers. These results suggest that a New World monkey model of acute ZIKV infection mimics the human disease, and is likely to be useful for testing of drug and vaccine candidates.

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Publisher Correction: Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

Scientific Reports ◽

10.1038/s41598-018-34068-5 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Maxim Seferovic ◽

Claudia Sánchez-San Martín ◽

Suzette D. Tardif ◽

Julienne Rutherford ◽

Eumenia C. C. Castro ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Fetal Loss ◽

Common Marmoset ◽

Zika Virus Infection ◽

Neurodevelopmental Abnormalities

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Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

Mediators of Inflammation ◽

10.1155/2020/9527147 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Yuyi Huang ◽

Yujie Wang ◽

Shuhui Meng ◽

Zhuohang Chen ◽

Haifan Kong ◽

...

Keyword(s):

Virus Infection ◽

Cell Line ◽

Zika Virus ◽

Fetal Brain ◽

Host Immunity ◽

Type I ◽

Type I Ifn ◽

Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

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A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

Human Molecular Genetics ◽

10.1093/hmg/ddz293 ◽

2019 ◽

Vol 29 (2) ◽

pp. 274-285 ◽

Cited By ~ 1

Author(s):

Roberto Costa ◽

Stefania Bellesso ◽

Susanna Lualdi ◽

Rosa Manzoli ◽

Valeria Pistorio ◽

...

Keyword(s):

Wnt Signaling ◽

Gaucher Disease ◽

Wnt Pathway ◽

Experimental Models ◽

Type I ◽

Loss Of Function ◽

Single Nucleotide Variants ◽

Bone Differentiation

Abstract Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

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A New In Vivo Model to Study Protective Immunity to Zika Virus Infection in Mice With Intact Type I Interferon Signaling

Frontiers in Immunology ◽

10.3389/fimmu.2018.00593 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 18

Author(s):

Loulieta Nazerai ◽

Amalie Skak Schøller ◽

Peter Overbeck Sharma Rasmussen ◽

Søren Buus ◽

Anette Stryhn ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Protective Immunity ◽

Type I Interferon ◽

In Vivo Model ◽

Type I ◽

Interferon Signaling ◽

Zika Virus Infection

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A susceptible mouse model for Zika virus infection

10.1101/042358 ◽

2016 ◽

Cited By ~ 1

Author(s):

Stuart D Dowall ◽

Victoria A Graham ◽

Emma Rayner ◽

Barry Atkinson ◽

Graham Hall ◽

...

Keyword(s):

Zika Virus ◽

Clinical Symptoms ◽

Natural Infection ◽

Viral Rna ◽

In Vivo Studies ◽

Type I ◽

Susceptible Mouse ◽

Zikv Infection ◽

Histological Changes

Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with viral RNA being detected widespread in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels to those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus a suitable small animal model for the testing of vaccines and antivirals which are urgently required.

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Lessons from experimental APS models

Lupus ◽

10.1177/096120339800700234 ◽

1998 ◽

Vol 7 (2_suppl) ◽

pp. 158-161 ◽

Cited By ~ 20

Author(s):

Y Shoenfeld ◽

L Ziporen

Keyword(s):

Renal Dysfunction ◽

Thrombus Formation ◽

Clinical Manifestations ◽

Fetal Loss ◽

Peripheral Blood Lymphocytes ◽

Experimental Models ◽

Histological Evaluation ◽

In Vivo Model ◽

Behavioral Impairments

Several animal models for antiphospholipid syndrome (APS) have been reported in the literature. These experimental models have contributed significantly in resolving enigmas in this multisystemic disease. We, and others have previously shown the pathogenicity of anticardiolipin (aCL) antibodies in pregnancy outcome. We have expanded our studies to show the pathogenicity of aCL antibodies in renal dysfunction and neurological and behavioral impairments in animals with experimental APS. Animals immunized with aCL or with the cofactor β2GPI developed clinical manifestations of APS, including fetal loss, thrombocytopenia and neurological and behavioral dysfunction, along with elevated levels of aPL antibodies. In another animal model, peripheral blood lymphocytes (PBLs) derived from APS patients could initiate APS manifestations with renal dysfunction in SCID mice. A unique in vivo model for thrombus formation was recently established to show the pathogenicity of aPL in thrombosis associated with APS. Histological evaluation of affected tissues derived from animals or from patients with APS have pointed to common mechanisms underlying APS, showing mainly thrombotic changes accompanied by mild inflammatory reaction.

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Rapid Construction of an Infectious Clone of the Zika Virus, Strain ZKC2

Frontiers in Microbiology ◽

10.3389/fmicb.2021.752578 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhiran Qin ◽

Yangyang Chen ◽

Jianhai Yu ◽

Xiaoen He ◽

Xuling Liu ◽

...

Keyword(s):

Homologous Recombination ◽

Zika Virus ◽

Infectious Clone ◽

Type I ◽

Global Public Health ◽

Mutation Site ◽

T7 Promoter ◽

Rna Transfection

Zika virus (ZIKV) has had detrimental effects on global public health in recent years. This is because the management of the disease has been limited, in part because its pathogenic mechanisms are not yet completely understood. Infectious clones are an important tool that utilize reverse genetics; these can be used to modify the ZIKV genomic RNA at the DNA level. A homologous recombination clone was used to construct pWSK29, a low copy plasmid that contained sequences for a T7 promoter, the whole genome of ZIKV ZKC2 strain, and a hepatitis delta virus ribozyme. High fidelity PCR was then used to amplify the T7 transcription template. The transcript was then transfected into susceptible cells via lipofection to recover the ZIKV ZKC2 strain. Finally, the virulence of rZKC2 was evaluated both in vitro and in vivo. The rZKC2 was successfully obtained and it showed the same virulence as its parent, the ZIKV ZKC2 strain (pZKC2), both in vitro and in vivo. The 3730 (NS2A-D62G) mutation site was identified as being important, since it had significant impacts on rZKC2 recovery. The 4015 (NS2A, A157V) mutation may reduce virus production by increasing the interferon type I response. In this study, one of the earliest strains of ZIKV that was imported into China was used for infectious clone construction and one possible site for antiviral medication development was discovered. The use of homologous recombination clones, of PCR products as templates for T7 transcription, and of lipofection for large RNA transfection could increase the efficiency of infectious clone construction. Our infectious clone provides an effective tool which can be used to explore the life cycle and medical treatment of ZIKV.

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