Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium

Simonin, Yannick; Erkilic, Nejla; Damodar, Krishna; Clé, Marion; Desmetz, Caroline; Bolloré, Karine; Taleb, Mehdi; Torriano, Simona; Barthélémy, Jonathan; Dubois, Gérard; Lajoix, Anne; Foulongne, Vincent; Tuaillon, Edouard; Perre, Philippe Van de; Kalatzis, Vasiliki; Salinas, Sara

doi:10.1016/j.ebiom.2018.12.010

Cited by 36 publications

(51 citation statements)

References 102 publications

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“…In addition, age, race, sex and other genetic and epigenetic factors of donor cells should be considered to determine common biological effect across a significant number of donors thereby avoiding minor variants (Lee et al, 2014;Zhang et al, 2013). (Table S1) (Ferreira et al, 2019;Iwasawa et al, 2019;Lanko et al, 2017;Simonin et al, 2019;Xia et al, 2017;Zhou et al, 2017).…”

Section: Evaluation Of Bsaas In Human Primary Cell Culture and Co-culmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

184

108

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# Contributed equally J o u r n a l P r e -p r o o f Highlights  We reviewed discovery and development process of broad-spectrum antiviral agents.  We summarized the information on 119 safe-in-man agents in freely accessible database.  Further studies will increase the number of broad-spectrum antivirals, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and reemerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. J o u r n a l P r e -p r o o f 2015). Antiviral drugs and vaccines are used to fight viral infections in human (De Clercq and Li, 2016; Marston et al., 2014). Previously, there has been a focus on "one drug, one virus" dogma, which relied on targeting virus-specific factors. A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015; de Clercq and Montgomery, 1983; Debing et al., 2015; Ianevski et al., 2019; Rada and Dragun, 1977; Sidwell et al., 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al., 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology. Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018; Pushpakom et al., 2019). This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in pre-clinical (animal model) and early clinical developmental phases (phase 0, I and IIa) are already available (Figure 1). Therefore, repositioning of launched or even failed drugs to viral diseases provides unique translational opportunities, includi...

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Section: Evaluation Of Bsaas In Human Primary Cell Culture and Co-culmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

184

108

View full text Add to dashboard Cite

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“…In these cells, viral replication could be associated with anti-viral responses and cytokine secretion, which could potentiate local inflammation. Human induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium is morphologically and functionally characteristic of the RPE in vivo and thus represents a powerful model for studying pathophysiology of the RPE and its role during arboviral infection [55,56]. We infected human RPE, grown on transwell filters in compartmentalized chambers, with USUV at a MOI of 0.2.…”

Section: Usuv Induces Inflammatory Responses In the Eye And Efficientmentioning

confidence: 99%

“…It thus represents a powerful tool to study the pathophysiology of the RPE. Anatomically and developmentally, the eyes are known as an extension of the CNS and are proposed to act as a reservoir of viral replication; moreover RPE are known to be targeted by numerous pathogens including arboviruses, such as DENV, ZIKV and WNV, leading to major ophthalmological damage [50,51,56,76]. Numerous studies have shown the critical role of immune cells in retinal disease, and neuroinflammation is an important aspect of many diseases of the eye.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Study of Usutu virus neuropathogenicity in mice and human cellular models

et al. 2020

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Usutu virus (USUV), an African mosquito-borne flavivirus closely related to West Nile virus, was first isolated in South Africa in 1959. USUV emerged in Europe two decades ago, causing notably massive mortality in Eurasian blackbirds. USUV is attracting increasing attention due to its potential for emergence and its rapid spread in Europe in recent years. Although mainly asymptomatic or responsible for mild clinical signs, USUV was recently described as being associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting the potential health threat posed by the virus. Despite this, USUV pathogenesis remains largely unexplored. The aim of this study was to evaluate USUV neuropathogenicity using in vivo and in vitro approaches. Our results indicate that USUV efficiently replicates in the murine central nervous system. Replication in the spinal cord and brain is associated with recruitment of inflammatory cells and the release of inflammatory molecules as well as induction of antiviral-responses without major modulation of bloodbrain barrier integrity. Endothelial cells integrity is also maintained in a human model of the blood-brain barrier despite USUV replication and release of pro-inflammatory cytokines. Furthermore, USUV-inoculated mice developed major ocular defects associated with inflammation. Moreover, USUV efficiently replicates in human retinal pigment epithelium. Our results will help to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence.

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“…Transepithelial resistance of the RPE, as well as cell junctions and, thus, RPE architecture, were impaired after ZIKV infection. As a follow-up of these observations, a strong inflammatory response, as revealed by induction of IFNs, was identified in RPE after ZIKV infection [110]. The relevance of inflammation as an effective host countermeasure against ZIKV infection is emphasized by the sex determining region Y (SRY)-box 2 (SOX2)-dependent susceptibility of glioblastoma stem cells, as SOX2 expression was associated with a reduced innate antiviral response [111].…”

Section: The Infection Of Pluripotent Stem Cell-based Models Of Humanmentioning

confidence: 89%

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Claus

Jung

Hübschen

2020

Cells

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The rubella virus (RV) was the first virus shown to be teratogenic in humans. The wealth of data on the clinical symptoms associated with congenital rubella syndrome is in stark contrast to an incomplete understanding of the forces leading to the teratogenic alterations in humans. This applies not only to RV, but also to congenital viral infections in general and includes (1) the mode of vertical transmission, even at early gestation, (2) the possible involvement of inflammation as a consequence of an activated innate immune response, and (3) the underlying molecular and cellular alterations. With the progress made in the development of pluripotent stem cell-based models including organoids and embryoids, it is now possible to assess congenital virus infections on a mechanistic level. Moreover, antiviral treatment options can be validated, and newly emerging viruses with a potential impact on human embryonal development, such as that recently reflected by the Zika virus (ZIKV), can be characterized. Here, we discuss human cytomegalovirus (HCMV) and ZIKV in comparison to RV as viruses with well-known congenital pathologies and highlight their analysis on current models for the early phase of human development. This includes the implications of their genetic variability and, as such, virus strain-specific properties for their use as archetype models for congenital virus infections. In this review, we will discuss the use of induced pluripotent stem cells (iPSC) and derived organoid systems for the study of congenital virus infections with a focus on their prominent aetiologies, HCMV, ZIKV, and RV. Their assessment on these models will provide valuable information on how human development is impaired by virus infections; it will also add new insights into the normal progression of human development through the analysis of developmental pathways in the context of virus-induced alterations. These are exciting perspectives for both developmental biology and congenital virology.

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Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium

Cited by 36 publications

References 102 publications

Discovery and development of safe-in-man broad-spectrum antiviral agents

Discovery and development of safe-in-man broad-spectrum antiviral agents

Study of Usutu virus neuropathogenicity in mice and human cellular models

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

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