Mechanisms of Zika Virus Infection and Neuropathogenesis

Olagnier, David; Muscolini, Michela; Coyne, Carolyn B.; Diamond, Michael S.; Hiscott, John

doi:10.1089/dna.2016.3404

Cited by 50 publications

(51 citation statements)

References 48 publications

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“…The numbers of people infected in these outbreaks were unprecedentedly high. More severe complications, including birth defects and neurological disorders, were observed (5,6). New modes of transmission, including blood-borne, transplacental, and sexual transmission, were also found (1,7).…”

mentioning

confidence: 92%

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Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Chaudhary

Yuen

Chan

et al. 2017

J Virol

101

112

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Severe complications of Zika virus (ZIKV) infection might be caused by inflammation, but how ZIKV induces proinflammatory cytokines is not understood. In this study, we show opposite regulatory effects of the ZIKV NS5 protein on interferon (IFN) signaling. Whereas ZIKV and its NS5 protein were potent suppressors of type I and type III IFN signaling, they were found to activate type II IFN signaling. Inversely, IFN-␥ augmented ZIKV replication. NS5 interacted with STAT2 and targeted it for ubiquitination and degradation, but it had no influence on STAT1 stability or nuclear translocation. The recruitment of STAT1-STAT2-IRF9 to IFN-␤-stimulated genes was compromised when NS5 was expressed. Concurrently, the formation of STAT1-STAT1 homodimers and their recruitment to IFN-␥-stimulated genes, such as the gene encoding the proinflammatory cytokine CXCL10, were augmented. Silencing the expression of an IFN-␥ receptor subunit or treatment of ZIKV-infected cells with a JAK2 inhibitor suppressed viral replication and viral induction of IFN-␥-stimulated genes. Taken together, our findings provide a new mechanism by which the ZIKV NS5 protein differentially regulates IFN signaling to facilitate viral replication and cause diseases. This activity might be shared by a group of viral IFN modulators.IMPORTANCE Mammalian cells produce three types of interferons to combat viral infection and to control host immune responses. To replicate and cause diseases, pathogenic viruses have developed different strategies to defeat the action of host interferons. Many viral proteins, including the Zika virus (ZIKV) NS5 protein, are known to be able to suppress the antiviral property of type I and type III interferons. Here we further show that the ZIKV NS5 protein can also boost the activity of type II interferon to induce cellular proteins that promote inflammation. This is mediated by the differential effect of the ZIKV NS5 protein on a pair of cellular transcription factors, STAT1 and STAT2. NS5 induces the degradation of STAT2 but promotes the formation of STAT1-STAT1 protein complexes, which activate genes controlled by type II interferon. A drug that specifically inhibits the IFN-␥ receptor or STAT1 shows an anti-ZIKV effect and might also have anti-inflammatory activity.KEYWORDS Zika virus, NS5 protein, type II interferon, STAT1, STAT2 Z ika virus (ZIKV) is a member of the Flaviviridae family with a positive-sense RNA genome of about 10 kb (1). Similar to other flaviviruses, such as yellow fever virus, dengue virus, and Japanese encephalitis virus, ZIKV expresses a single polypeptide which is proteolytically processed into 3 structural (C, prM, and E) and 7 nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. ZIKV is an arbovirus transmitted to humans through the bites of mosquitoes of the species Aedes aegypti and, to a lesser extent, Aedes albopictus (2). Since its discovery in 1947 (3), ZIKV had been known to cause only mild and self-limiting febrile diseases, with a majority of patients being

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mentioning

confidence: 92%

“…Although it remains to be determined whether mutations have enabled ZIKV to become more pathogenic and transmissible (19), innate immunity is thought to govern both viral replication and pathogenesis (6,20). Indeed, innate antiviral effectors, such as type I and type III interferons (IFNs), are capable of suppressing ZIKV replication (21,22).…”

mentioning

confidence: 99%

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Chaudhary

Yuen

Chan

et al. 2017

J Virol

101

112

View full text Add to dashboard Cite

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“…Olagnier et al [72] have suggested that the viral infection of fetal neural progenitor cells could activate TLR3 immune responses, leading to a deregulation of genes that control apoptosis, resulting in severe damage to the embryonic brain. All of these inflammatory issues are relevant when it comes to a viral infection since the immune system may respond differently.…”

Section: Neuroimmunomodulation Of Asd and Zikvmentioning

confidence: 99%

Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects

Vianna

Gomes

Boquett

et al. 2018

Neuroimmunomodulation

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The recent outbreak of the Zika virus (ZIKV) and the discovery that perinatal Zika exposure can lead to the Congenital Zika Syndrome has promoted a call for prevention measures. Due to the increased number of babies born with microcephaly, structural brain abnormalities, and neurological alterations in regions affected by ZIKV, investigations were carried out in order to better understand this process. The maternal immune system directly influences the fetal central nervous system, and complications during pregnancy have been associated with neurodevelopmental disorders. Autism spectrum disorder (ASD), a neurodevelopmental disorder commonly manifested in the first years of life, is a disease with multifactorial etiology and is manifested typically by social and communication impairments, as well as stereotyped behaviors. Brain abnormalities, including both anatomically and functionally, can be observed in this disorder, suggesting delays in neuronal maturation and altered brain connectivity. It is known that some viral congenital infections, such as rubella, and cytomegalovirus can interfere with brain development, being associated with brain calcification, microcephaly, and ASD. Here, we reviewed a range of studies evaluating the aspects concerning brain development, immunological status during pregnancy, and neuroimmunomodulation in congenital viral infections, and we discuss if the fetal brain infection caused by ZIKV could predispose to ASD. Finally, we suggest a mechanism encompassing neurological and immunological pathways that could play a role in the development of ASD in infants after ZIKV infection in pregnancy.

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“…The transplacental transmission of Zika virus from mother to foetus may occur by the infection of placental macrophages (Hofbauer cells) and cytotrophoblasts [59]. Macrophages are the main target cells of Zika viral infection in the placenta [60]. Viral infection in placental macrophages induces the production of type I interferon and pro-inflammatory cytokines resulting in an antiviral gene expression [60].…”

Section: Possible Molecular Events Leading To Microcephalymentioning

confidence: 99%

“…Macrophages are the main target cells of Zika viral infection in the placenta [60]. Viral infection in placental macrophages induces the production of type I interferon and pro-inflammatory cytokines resulting in an antiviral gene expression [60]. …”

Section: Possible Molecular Events Leading To Microcephalymentioning

confidence: 99%

Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism

et al. 2016

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Zika virus is an arthropod-borne re-emerging pathogen associated with the global pandemic of 2015-2016. The devastating effect of Zika viral infection is reflected by its neurological manifestations such as microcephaly in newborns. This scenario evoked our interest to uncover the neurotropic localization, multiplication of the virus, and the mechanism of microcephaly. The present report provides an overview of a possible molecular mechanism of Zika virus-induced microcephaly based on recent publications. Transplacental transmission of Zika viral infection from mother to foetus during the first trimester of pregnancy results in propagation of the virus in human neural progenitor cells (hNPCs), where entry is facilitated by the receptor (AXL protein) leading to the alteration of signalling and immune pathways in host cells. Further modification of the viral-induced TLR3-mediated immune network in the infected hNPCs affects viral replication. Downregulation of neurogenesis and upregulation of apoptosis in hNPCs leads to cell cycle arrest and death of the developing neurons. In addition, it is likely that the environmental, physiological, immunological, and genetic factors that determine in utero transmission of Zika virus are also involved in neurotropism. Despite the global concern regarding the Zika-mediated epidemic, the precise molecular mechanism of neuropathogenesis remains elusive.

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Mechanisms of Zika Virus Infection and Neuropathogenesis

Cited by 50 publications

References 48 publications

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Selective Activation of Type II Interferon Signaling by Zika Virus NS5 Protein

Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects

Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism

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