Acute and chronic neurological consequences of early-life Zika virus infection in mice

Souza, Isis Nem de Oliveira; Frost, Paula S.; França, Júlia V.; Nascimento-Viana, Jéssica Barbosa; Neris, Rômulo L. S.; Oliveira, Leandro Freitas; Pinheiro, Daniel J. L. L.; Nogueira, Clara O.; Neves, Gilda; Chimelli, Leila; Felice, Fernanda G. De; Cavalheiro, Ésper A.; Ferreira, Sérgio T.; Assunção‐Miranda, Iranaia; Figueiredo, Cláudia P.; Poian, Andrea T. Da; Clarke, Julia R.

doi:10.1126/scitranslmed.aar2749

Cited by 99 publications

(78 citation statements)

References 56 publications

(74 reference statements)

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“…These findings as well as the smaller cerebellum GM volumes may explain the increased incidents of balance loss seen amongst the ZIKV-infected infant RMs during their exploration of a novel social environment. Although we did not perform a specific test of gross motor function, our current findings of uncoordinated movements resulting in losses of balance suggest that postnatal ZIKV infection may have impacted motor development and psychomotricity, which has also been demonstrated in a murine model of postnatal ZIKV infection 71 .…”

Section: Discussionmentioning

confidence: 62%

“…There have been conflicting reports on the neurologic complications and neurodevelopmental outcomes of children exposed to ZIKV in the peripartum and postnatal periods [26][27][28][29][30] . Studies with large numbers of cases have yet to be published, while research in animal models suggest that ZIKV infection during the postnatal period may also have a deleterious impact on development 31,32 . We recently demonstrated in infant rhesus macaques (RMs) that postnatal infection with ZIKV disseminates to the central and peripheral nervous systems with histologic features in the post-mortem brain similar to prenatal ZIKV infection 31 .…”

Section: Mainmentioning

confidence: 99%

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Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Raper

Kovacs-Balint

Mavinger

et al. 2019

Preprint

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Considering the impact that Zika virus (ZIKV) infection has on the fetal nervous system and given that the postnatal period is also a time of rapid brain growth, it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Using a rhesus macaque (RM) model, we showed that postnatal ZIKV infection resulted in long-term behavioral changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant RMs had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior and cognitive function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection of infants in this model has long lasting neurodevelopmental consequences.

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Section: Discussionmentioning

confidence: 62%

Section: Mainmentioning

confidence: 99%

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Raper

Kovacs-Balint

Mavinger

et al. 2019

Preprint

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“…To study these questions on Zika virus pathogenesis, various animal models have been developed, most of which use immune deficient mice that are susceptible to Zika virus infection in vivo such as A129 (129 background, deficient in IFN-α/β receptor), AG129 (129 background, deficient in IFN-α/β and IFN-γ receptors), A6 (C57/BL6 background, deficient in IFN-α/β receptor), AG6 (C57/BL6 background, deficient in IFN-α/β and IFN-γ receptors); Stat2 deficient mice, and Rag1 deficient mice (13,27–30). Zika virus can also infect wild type neonatal mice and cause diseases that resemble to some extent microcephaly, paralysis, and seizure (31–33). Mechanistically, these neurological manifestations have been linked to Zika virus infection of neuron progenitor cells and other neurocytes in neonatal mice in vivo (11,17,34).…”

Section: Introductionmentioning

confidence: 99%

A single nonsynonymous mutation on gene encoding E protein of Zika virus leads to increased neurovirulence in vivo

Cheng

et al. 2020

Preprint

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Recent large outbreaks of Zika virus infection worldwide have revealed an 60 association between the viral infection and increased cases of specific 61 neurological problems including Congenital Zika Syndrome (including 62 microcephaly) and adult Guillain-Barré Syndrome. However, the determinants 63 of the increased neurovirulence of Zika virus remain uncertain. One hypothesis 64 is that some unique changes across the Zika viral genome have led to the 65 occurrence of these neurological diseases. To test this hypothesis, we 66 continuously propagated a clinical isolate of contemporary Zika virus (SW01) in 67 neonatal mice brain for 11 times to obtain an mouse central nervous system 68 (CNS) adapted Zika virus (MA-SW01) that showed significantly increased 69 neurovirulence in vivo. We then discovered that a single G to A nucleotide 70 substitution at the 1069 site of Zika virus open reading frame leading to a D 71 (aspartic acid) to N (asparagine) in viral Envelope protein is responsible for the 72 increased neurovirulence. These findings improve our understanding of the 73 neurological pathogenesis of Zika virus and provide clues for the development 74 of antiviral strategy. 75 76 77 78 79 80 81 82 83 84 85 86 87 5 / 32

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“…It has been demonstrated that ZIKV replicates in human neural progenitor cells and brain organoids, resulting in cell death and cell cycle arrest (7, 8). Both intra-uterine and neonatal ZIKV exposure in mice was shown to compromise neurogenesis and cause severe necrosis in different brain regions, along with persistent viral replication and widespread neuroinflammation (9, 10). Moreover, it was shown that activation of microglial cells and astrocytes associated to viral replication in the brain affects cognitive function and the differentiation of glial progenitors cells impairing brain development (11, 12).…”

Section: Introductionmentioning

confidence: 99%

Zika virus replicates in skeletal muscle contributing to peripheral viral amplification prior to reach neural tissue

Gavino-Leopoldino

et al. 2020

Preprint

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Zika virus (ZIKV) infections are still a worldwide concern due to the severity of neurological outcomes. ZIKV neurotropism is well characterized, but peripheral tissue could be sites of viral amplification, contributing to endothelial-barrier crossing and access to peripheral nerves. During acute and late phases of infection, ZIKV can be detected in several body fluids, eyes, testis and vagina. However, the importance of initial replication sites for the establishment of infection and viral spread remain unknown. Here we demonstrated that ZIKV replicates primarily in human muscle precursor cells, resulting in cell death and inhibition of myogenesis. ZIKV also replicates in fetal muscle after maternal transmission and in infected neonate mice, inducing lesions and inflammation. Muscle was an important site of viral amplification, sustaining higher peripheral viral loads than liver and spleen. In addition, ZIKV showed rapid and sustained replication kinetics in muscle even before replication in the neural tissues, persisting until 16 days post infection. Our results highlight the importance of muscle in ZIKV pathogenesis as a peripheral site of viral amplification which may contribute to ZIKV reaching neural structures.Author SummaryZika Virus (ZIKV) neurotropism and its deleterious effects on central nervous system have been well characterized. But, investigations of the initial replication sites for the establishment of infection and viral spread to neural tissues remain under explored. Here we demonstrated that ZIKV replicates primarily in human skeletal muscle precursor cells, resulting in cell death and disrupted myogenesis. ZIKV also replicates in muscle of fetus and neonate mice inducing muscle damage and inflammation. Muscle replication occurs before amplification in peripheral nerves and brain, contributing to the increase of peripheral ZIKV load and dissemination. In addition, ZIKV RNA still been detected in skeletal muscle at late stages of infection. Overall, our findings showed that skeletal muscle is involved in ZIKV pathogenesis, contributing to a broader understanding of ZIKV infection. Thus, opens new aspects in the investigation of the long-term consequence of early infection.

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Acute and chronic neurological consequences of early-life Zika virus infection in mice

Cited by 99 publications

References 56 publications

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

A single nonsynonymous mutation on gene encoding E protein of Zika virus leads to increased neurovirulence in vivo

Zika virus replicates in skeletal muscle contributing to peripheral viral amplification prior to reach neural tissue

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