Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

ABSTRACTZika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

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Faculty Opinions recommendation of Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727327812.793534615 ◽

2017 ◽

Author(s):

Philippe Le Bouteiller

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Perinatal Outcomes ◽

Transplacental Transmission ◽

Zika Virus Infection ◽

Adverse Perinatal Outcomes ◽

Immunocompetent Mice

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Faculty Opinions recommendation of Zika virus outbreak: a review of neurological complications, diagnosis, and treatment options.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732666093.793581255 ◽

2020 ◽

Author(s):

Tian Wang

Keyword(s):

Zika Virus ◽

Treatment Options ◽

Neurological Complications ◽

Diagnosis And Treatment

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

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200602140005 ◽

2020 ◽

Vol 21 ◽

Cited By ~ 1

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.

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Gut microbiota modulation induced by Zika virus infection in immunocompetent mice

Scientific Reports ◽

10.1038/s41598-020-80893-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rafael Corrêa ◽

Igor de Oliveira Santos ◽

Heloísa Antoniella Braz-de-Melo ◽

Lívia Pimentel de Sant’Ana ◽

Raquel das Neves Almeida ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Zika Virus ◽

Hypervariable Region ◽

Microbiota Composition ◽

Colon Tissue ◽

Zikv Infection ◽

Immunological Responses ◽

Immunocompetent Mice ◽

Gut Microbiota Composition

AbstractGut microbiota composition can modulate neuroendocrine function, inflammation, and cellular and immunological responses against different pathogens, including viruses. Zika virus (ZIKV) can infect adult immunocompetent individuals and trigger brain damage and antiviral responses. However, it is not known whether ZIKV infection could impact the gut microbiome from adult immunocompetent mice. Here, we investigated modifications induced by ZIKV infection in the gut microbiome of immunocompetent C57BL/6J mice. Adult C57BL/6J mice were infected with ZIKV and the gut microbiota composition was analyzed by next-generation sequencing of the V4 hypervariable region present in the bacterial 16S rDNA gene. Our data showed that ZIKV infection triggered a significant decrease in the bacteria belonging to Actinobacteria and Firmicutes phyla, and increased Deferribacteres and Spirochaetes phyla components compared to uninfected mice. Interestingly, ZIKV infection triggered a significant increase in the abundance of bacteria from the Spirochaetaceae family in the gut microbiota. Lastly, we demonstrated that modulation of microbiota induced by ZIKV infection may lead to intestinal epithelium damage and intense leukocyte recruitment to the intestinal mucosa. Taken together, our data demonstrate that ZIKV infection can impact the gut microbiota composition and colon tissue homeostasis in adult immunocompetent mice.

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Neurological Complications of Congenital Zika Virus Infection

Pediatric Neurology ◽

10.1016/j.pediatrneurol.2018.11.003 ◽

2019 ◽

Vol 91 ◽

pp. 3-10 ◽

Cited By ~ 13

Author(s):

Vinícius de Melo Marques ◽

Camilla Sousa Santos ◽

Isabella Godinho Santiago ◽

Solomar Martins Marques ◽

Maria das Graças Nunes Brasil ◽

...

Keyword(s):

Virus Infection ◽

Zika Virus ◽

Neurological Complications ◽

Zika Virus Infection

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Transmission dynamics of Zika virus in island populations: a modelling analysis of the 2013-14 French Polynesia outbreak

10.1101/038588 ◽

2016 ◽

Cited By ~ 13

Author(s):

Adam J. Kucharski ◽

Sebastian Funk ◽

Rosalind M. Eggo ◽

Henri-Pierre Mallet ◽

W. John Edmunds ◽

...

Keyword(s):

South America ◽

Dengue Virus ◽

Zika Virus ◽

French Polynesia ◽

Neurological Complications ◽

Transmission Dynamics ◽

Guillain Barre Syndrome ◽

Island Populations ◽

The Pacific ◽

Guillain Barré

AbstractBetween October 2013 and April 2014, more than 30,000 cases of Zika virus (ZIKV) disease were estimated to have attended healthcare facilities in French Polynesia. ZIKV has also been reported in Africa and Asia, and in 2015 the virus spread to South America and the Caribbean. Infection with ZIKV has been associated with neurological complications including Guillain-Barré Syndrome (GBS) and microcephaly, which led the World Health Organization to declare a Public Health Emergency of International Concern in February 2015. To better understand the transmission dynamics of ZIKV, we used a mathematical model to examine the 2013–14 outbreak on the six major archipelagos of French Polynesia. Our median estimates for the basic reproduction number ranged from 2.6–4.8, with an estimated 11.5% (95% CI: 7.32–17.9%) of total infections reported. As a result, we estimated that 94% (95% CI: 91–97%) of the total population of the six archipelagos were infected during the outbreak. Based on the demography of French Polynesia, our results imply that if ZIKV infection provides complete protection against future infection, it would take 12–20 years before there are a sufficient number of susceptible individuals for ZIKV to reemerge, which is on the same timescale as the circulation of dengue virus serotypes in the region. Our analysis suggests that ZIKV may exhibit similar dynamics to dengue virus in island populations, with transmission characterized by large, sporadic outbreaks with a high proportion of asymptomatic or unreported cases.Author SummarySince the first reported major outbreak of Zika virus disease in Micronesia in 2007, the virus has caused outbreaks throughout the Pacific and South America. Transmitted by the Aedes species of mosquitoes, the virus has been linked to possible neurological complications including Guillain-Barre Syndrome and microcephaly. To improve our understanding of the transmission dynamics of Zika virus in island populations, we analysed the 2013–14 outbreak on the six major archipelagos of French Polynesia. We found evidence that Zika virus infected the majority of population, but only around 12% of total infections on the archipelagos were reported as cases. If infection with Zika virus generates lifelong immunity, we estimate that it would take at least 15–20 years before there are enough susceptible people for the virus to reemerge. Our results suggest that Zika virus could exhibit similar dynamics to dengue virus in the Pacific, producing large but sporadic outbreaks in small island populations.

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Pregnancy and Zika virus

Obstetrics Gynecology and Reproduction ◽

10.17749/2313-7347.116 ◽

2020 ◽

Vol 14 (2) ◽

pp. 229-238

Author(s):

T. V. Startseva ◽

N. N. Kanshina ◽

M. V. Tretyakova ◽

V. O. Bitsadze ◽

J. Kh. Khizroeva ◽

...

Keyword(s):

Nonhuman Primate ◽

Zika Virus ◽

Congenital Malformations ◽

Asymptomatic Carrier ◽

Clinical Signs ◽

Neurological Complications ◽

Zikv Infection ◽

Coronavirus Infection ◽

Novel Coronavirus ◽

Urban Cycle

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) in the genus Flavivirus and the Flaviviridae family. In 1947 and 1948 ZIKV was first isolated from a nonhuman primate as well as from mosquitoes in Africa, respectively. For half a century, ZIKV infections in human were sporadic prior to 2015–2016 pandemic spreading. Transmission of ZIKV from mother to fetus can occur in any trimester of pregnancy, even if mother was an asymptomatic carrier. The clinical signs of ZIKV infection are nonspecific and can be misdiagnosed as some other infectious diseases, especially those caused by arboviruses such as Dengue and Chikungunya. ZIKV infection was solely associated with mild illness prior to the large French Polynesian and Brazil outbreaks, when severe neurological complications, Guillain–Barre syndrome and dramatically increased rate of severe congenital malformations (including microcephaly) were reported. The adaptation of ZIKV to an urban cycle in endemic areas suggests that the incidence of ZIKV infections may be underestimated. The pandemic of novel coronavirus infection (COVID-19) demonstrates that lessons from ZIKV pandemic propagation has not been learned properly.

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