Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons

The ability of viruses to evade the host antiviral immune system determines their level of replication fitness, species specificity, and pathogenic potential. Flaviviruses rely on the subversion of innate immune barriers including the type I and type III IFN antiviral systems. Zika virus infection induces the degradation of STAT2, an essential component of the IFN stimulated gene transcription factor, ISGF3. The mechanisms that lead to STAT2 degradation by Zika virus are poorly understood, but it is known to be mediated by the viral NS5 protein that binds to STAT2 and targets it for proteasome-mediated destruction. To better understand how NS5 engages and degrades STAT2, functional analysis of the protein interactions that lead to Zika virus and NS5-dependent STAT2 proteolysis were investigated. Data implicate the STAT2 coiled-coil domain as necessary and sufficient for NS5 interaction and proteasome degradation after Zika virus infection. Molecular dissection reveals that the first two α-helices of the STAT2 coiled-coil contain a specific targeting region for IFN antagonism. These functional interactions provide a more complete understanding of the essential protein-protein interactions needed for Zika virus evasion of the host antiviral response, and identifies new targets for antiviral therapeutic approaches. Importance Zika virus infection can cause mild fever, rash, and muscle pain, and in rare cases lead to brain or nervous system diseases including Guillain–Barré syndrome. Infections in pregnant women can increase the risk of miscarriage or serious birth defects including brain anomalies and microcephaly. There are no drugs or vaccines for Zika disease. Zika virus is known to break down the host antiviral immune response, and this research project reveals how the virus suppresses interferon signaling, and may reveal therapeutic vulnerabilities.

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Shiftless inhibits flavivirus replication in vitro and is neuroprotective in a mouse model of Zika virus pathogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111266118 ◽

2021 ◽

Vol 118 (49) ◽

pp. e2111266118

Author(s):

Natasha W. Hanners ◽

Katrina B. Mar ◽

Ian N. Boys ◽

Jennifer L. Eitson ◽

Pamela C. De La Cruz-Rivera ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Virus Infection ◽

Mouse Model ◽

Viral Replication ◽

Zika Virus ◽

Type I ◽

West Nile ◽

Zika Virus Infection ◽

The Central Nervous System

Flaviviruses such as Zika virus and West Nile virus have the potential to cause severe neuropathology if they invade the central nervous system. The type I interferon response is well characterized as contributing to control of flavivirus-induced neuropathogenesis. However, the interferon-stimulated gene (ISG) effectors that confer these neuroprotective effects are less well studied. Here, we used an ISG expression screen to identify Shiftless (SHFL, C19orf66) as a potent inhibitor of diverse positive-stranded RNA viruses, including multiple members of the Flaviviridae (Zika, West Nile, dengue, yellow fever, and hepatitis C viruses). In cultured cells, SHFL functions as a viral RNA-binding protein that inhibits viral replication at a step after primary translation of the incoming genome. The murine ortholog, Shfl, is expressed constitutively in multiple tissues, including the central nervous system. In a mouse model of Zika virus infection, Shfl−/− knockout mice exhibit reduced survival, exacerbated neuropathological outcomes, and increased viral replication in the brain and spinal cord. These studies demonstrate that Shfl is an important antiviral effector that contributes to host protection from Zika virus infection and virus-induced neuropathological disease.

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The Human STAT2 Coiled-Coil Domain Contains a Degron for Zika Virus Interferon Evasion

10.1101/2021.10.01.462781 ◽

2021 ◽

Author(s):

Jean-Patrick Parisien ◽

Jessica J Lenoir ◽

Gloria Alvarado ◽

Curt M Horvath

Keyword(s):

Virus Infection ◽

Protein Interactions ◽

Zika Virus ◽

Coiled Coil ◽

Type I ◽

Protein Protein Interactions ◽

Pathogenic Potential ◽

Coiled Coil Domain ◽

Zika Virus Infection ◽

Type Iii Ifn

The ability of viruses to evade the host antiviral immune system determines their level of replication fitness, species specificity, and pathogenic potential. Flaviviruses rely on the subversion of innate immune barriers including the type I and type III IFN antiviral systems. Zika virus infection induces the degradation of STAT2, an essential component of the IFN stimulated gene transcription factor, ISGF3. The mechanisms that lead to STAT2 degradation by Zika virus are poorly understood, but it is known to be mediated by the viral NS5 protein that binds to STAT2 and targets it for proteasome-mediated destruction. To better understand how NS5 engages and degrades STAT2, functional analysis of the protein interactions that lead to Zika virus and NS5-dependent STAT2 proteolysis were investigated. Data implicate the STAT2 coiled-coil domain as necessary and sufficient for NS5 interaction and proteasome degradation after Zika virus infection. Molecular dissection reveals that the first two α-helices of the STAT2 coiled-coil contain a specific targeting region for IFN antagonism. These functional interactions provide a more complete understanding of the essential protein-protein interactions needed for Zika virus evasion of the host antiviral response, and identifies new targets for antiviral therapeutic approaches.

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Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

10.1101/050674 ◽

2016 ◽

Author(s):

Zachary A. Klase ◽

Svetlana Khakhina ◽

Adriano De Bernardi Schneider ◽

Michael V Callahan ◽

Jill Glasspool-Malone ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Neutralizing Antibody ◽

Type I ◽

List Type ◽

Teratogenic Effects ◽

Viral Pathogen ◽

Regulatory Pathways ◽

Zika Virus Infection ◽

Autoimmune Pathology

AbstractThe ongoing Zika Virus epidemic in the Americas, and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain-Barré syndrome) has brought attention to this neglected pathogen. While initial case studies generated significant interest in the Zika virus outbreak, larger prospective epidemiology and basic virology studies examining the mechanisms of Zika viral infection and associated pathophysiology are only now starting to be published. In this review, we analyze Zika fetal neuropathogenesis from a comparative pathology perspective, using the historic metaphor of “TORCH” viral pathogenesis to provide context. By drawing parallels to other viral infections of the fetus, we identify common themes and mechanisms that may illuminate the observed pathology. The existing data on the susceptibility of various cells to both Zika and other flavivirus infections are summarized. Finally, we highlight relevant aspects of the known molecular mechanisms of flavivirus replication.Key Learning PointsViral TORCH pathogens reveal common patterns of fetal pathophysiology and vertical transmission which are relevant to Zika Virus fetal neuropathogenesis.The teratogenic effects of Zika Virus infection during the first trimester may involve infection of the trophoblast, viral translocation across the placenta, migration of infected cells resulting in embryonic infection, or indirect effects associated with high levels of inflammatory cytokines produced by infected placenta.Pre-existing maternal non-neutralizing antibody to Zika virus may enhance the probability of infection or more severe disease in the fetus.AXL has been identified as a major receptor for Zika Virus.Zika virus activation of Toll Like Receptor 3 (TLR-3) pathways in central nervous system cells may trigger apoptosis and attenuate neurogenesis, directly contributing to fetal neuropathology.Flaviviruses subvert host autophagy and noncoding RNA regulatory pathways.Recognition of viral sequences by regulatory RNA binding proteins such as Musashi may have a role in Zika pathogenesis and host tissue tropism.Evidence from other TORCH viral pathogen studies indicate multiple plausible hypotheses for transplacental infection by Zika virus during the second or third trimester, including transcytosis of non-neutralizing antibody-coated Zika virus complexes.Key ReferencesAdibi JJ, Marques ET Jr, Cartus A, Beigi RH. Teratogenic effects of the Zika virus and the role of the placenta. Lancet 2016; 387: 1587–90 (Hypothesis)Adams Waldorf KM, McAdams RM. Influence of infection during pregnancy on fetal development. Reproduction. 2013 Oct 1;146(5) (Review)Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol. 2015;89(17):8880–96.Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika Virus Associated with Microcephaly. N Engl J Med. 2016 Feb 10.Paul LM, Carlin ER, Jenkins MM, Tan AL, Barcellona CM, Nicholson CO, Trautmann L, Michael SF, Isern S. Dengue Virus Antibodies Enhance Zika Virus Infection. bioRxiv doi:http://dx.doi.org/10.1101/050112Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429-40.Tonduti D, Orcesi S, Jenkinson EM, Dorboz I, Renaldo F, Panteghini C, et al. Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutieres syndrome. Eur J Paediatr Neurol. 2016.Cipolat Mis MS, Brajkovic S, Frattini E, Di Fonzo A, Corti S. Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets. Molecular and Cellular Neurosciences. 2016;72:84-90.Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, Rana TM. Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. Cell Stem Cell. 2016: 19: 1–8.Vianna FS, Schuler-Faccini L, Leite JC, de Sousa SH, da Costa LM, Dias MF, et al. Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. Clin Dysmorphol. 2013;22(2):59-63.

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Yellow Fever Vaccine Protects Resistant and Susceptible Mice Against Zika Virus Infection

10.1101/587444 ◽

2019 ◽

Author(s):

Ana C. Vicente Santos ◽

Francisca H. Guedes-da-Silva ◽

Carlos H. Dumard ◽

Vivian N. S. Ferreira ◽

Igor P. S. da Costa ◽

...

Keyword(s):

Viral Load ◽

Virus Infection ◽

Yellow Fever ◽

Zika Virus ◽

Large Scale ◽

Yellow Fever Virus ◽

Yellow Fever Vaccine ◽

Effective Vaccine ◽

Type I ◽

Zika Virus Infection

AbstractZika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. The development of an effective vaccine against Zika virus is a public health priority, encouraging the preclinical and clinical studies of different vaccine strategies. Here, we describe the protective effect of an already licensed attenuated yellow fever vaccine (17DD) on type-I interferon receptor knockout mice (A129) and immunocompetent (BALB/c) mice infected with ZIKV. Yellow fever virus vaccination results in robust protection against ZIKV, with decreased mortality in the A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in the BALB/c mice. Despite the limitation of yellow fever (17DD) vaccine to elicit antibody production and neutralizing activity against ZIKV, we found that YF immunization prevented the development of neurological impairment induced by intracerebral virus inoculation in adult. Although we used two vaccine doses in our protocol, a single dose was protective, reducing the cerebral viral load. Different Zika virus vaccine models have been tested; however, our work shows that an efficient and certified vaccine, available for use for several decades, effectively protects mice against Zika virus infection. These findings open the possibility for using an available and inexpensive vaccine to a large-scale immunization in the event of a Zika virus outbreak.

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Lineage-dependent differences in the disease progression of Zika virus infection in type-I interferon receptor knockout (A129) mice

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0005704 ◽

2017 ◽

Vol 11 (7) ◽

pp. e0005704 ◽

Cited By ~ 40

Author(s):

Stuart D. Dowall ◽

Victoria A. Graham ◽

Emma Rayner ◽

Laura Hunter ◽

Barry Atkinson ◽

...

Keyword(s):

Virus Infection ◽

Disease Progression ◽

Zika Virus ◽

Type I Interferon ◽

Type I ◽

Zika Virus Infection ◽

Interferon Receptor

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Congenital Zika Virus Infection Paradigm: What is in the Wardrobe? A Narrative Review

East Africa Science ◽

10.24248/easci.v1i1.4 ◽

2019 ◽

Vol 1 (1) ◽

pp. 49-56

Author(s):

Mariam M. Mirambo ◽

Lucas Matemba ◽

Mtebe Majigo ◽

Stephen E. Mshana

Keyword(s):

Virus Infection ◽

Neural Tube ◽

Zika Virus ◽

English Language ◽

Case Reports ◽

Case Series ◽

Epidemiological Studies ◽

Ocular Manifestations ◽

Zika Virus Infection ◽

N 93

Background: Zika virus infection during pregnancy has been recently associated with congenital microcephaly and other severe neural tube defects. However, the magnitude of confirmed cases and the scope of these anomalies have not been extensively documented. This review focuses on the magnitude of laboratory-confirmed congenital Zika virus cases among probable cases and describing the patterns of congenital anomalies allegedly caused by the Zika virus, information which will inform further research in this area. Methods: We conducted a literature search for English-language articles about congenital Zika virus infection using online electronic databases (PubMed/MEDLINE, POPLINE, Embase, Google Scholar, and Web of Knowledge). The search terms used were, “zika”, “pregnancy”, [year], “microcephaly”, “infants”, “children”, “neonates”, “foetuses”, “neural tube defect”, and “CNS manifestations” in different combinations. All articles reporting cases or case series between January 2015 and December 2016 were included. Data were entered into a Microsoft Excel database and analysed to obtain proportions of the confirmed cases and patterns of anomalies. Results: A total of 24 articles (11 case series, 9 case reports, and 4 others) were found to be eligible and included in this review. These articles reported 919 cases, with or without microcephaly, presumed to have congenital Zika virus infection. Of these cases, 884 (96.2%) had microcephaly. Of the 884 cases of microcephaly, 783 (88.6%) were tested for Zika virus infection, and 216 (27.6%; 95% confidence interval, 24.5% to 30.8%) were confirmed to be Zika virus-positive. In addition to microcephaly, other common abnormalities reported – out of 442 cases investigated – were calcifications of brain tissue (n=240, 54.3%), ventriculomegaly (n=93, 20.8%), cerebellar hypoplasia (n=52, 11.7%), and ocular manifestations (n=46, 10.4%). Conclusion: Based on the available literature, Zika virus infection during pregnancy might lead to a wide array of outcomes other than microcephaly. There is a need for more epidemiological studies in Zika-endemic areas, particularly in Africa, to ascertain the role of Zika virus in causing congenital neurological defects.

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