Determination of system level alterations in host transcriptome due to Zika virus (ZIKV) Infection in retinal pigment epithelium

Singh, Pawan Kumar; Khatri, Indu; Jha, Alokkumar; Pretto, Carla D.; Spindler, Katherine R.; Arumugaswami, Vaithilingaraja; Giri, Shailendra; Kumar, Ashok; Bhasin, Manoj

doi:10.1038/s41598-018-29329-2

Cited by 40 publications

(49 citation statements)

References 68 publications

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“…Accordingly, the data from RNA sequencing revealed few downregulated genes associated with the regulation of cell proliferation and apoptosis. These results are consistent with previous studies on ZIKV-infected human cell types, such as Sertoli cells in the seminiferous tubules, retinal pigment epithelium, neural progenitors, and astrocytes, which reported suppression of cell proliferation, as well as induction of antiviral defense pathways [24][25][26][27] .…”

Section: Discussionsupporting

confidence: 93%

Zika virus targets the human thymic epithelium

Messias

Loss-Morais

Carvalho

et al. 2020

Sci Rep

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Previous work showed that the thymus can be infected by RNA viruses as HIV and HTLV-1. We thus hypothesized that the thymus might also be infected by the Zika virus (ZIKV). Herein we provide compelling evidence that ZIKV targets human thymic epithelial cells (TEC) in vivo and in vitro. ZIKVinfection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, ZIKV modulates a high amount of coding RNAs with upregulation of genes related to cell adhesion and migration, as well as non-coding genes including miRNAs, circRNAs and lncRNAs. Moreover, we observed enhanced attachment of lymphoblastic T-cells to infected TEC, as well as virus transfer to those cells. Lastly, alterations in thymuses from babies congenitally infected were seen, with the presence of viral envelope protein in TEC. Taken together, our data reveals that the thymus, particularly the thymic epithelium, is a target for the ZIKV with changes in the expression of molecules that are relevant for interactions with developing thymocytes. Zika virus (ZIKV) epidemics in 2015-2016 resulted in devastating effects, causing microcephaly, other related congenital defects at birth and neurodevelopmental delay after two years in children born from mothers infected by the virus during pregnancy 1-4. Additionally, ZIKV infection in adults correlated with a rise in the frequency of cases of Guillain-Barré syndrome 5,6. Although the knowledge on the cellular and molecular alterations caused by the ZIKV in the nervous tissue largely increased in the last few years 2,7,8 , the effects of this virus upon hematopoietic tissues are much less defined. In terms of secondary lymphoid organs, ZIKV RNA and protein have been described in lymph nodes of Rhesus monkeys in both paracortex and germinal centers 9,10. The virus was also found in macrophages, dendritic cells, and B-cells, in both spleen and axillary lymph nodes of this non-human primate. However, in the same study, the presence of ZIKV RNA in T-cells was observed only in axillary lymph nodes from one animal 10. Much less is known on the putative infection of primary lymphoid organs, and more particularly in the thymus. This central lymphoid organ is responsible for the generation of T lymphocytes under the control of the thymic microenvironment, a three-dimensional cellular network mainly composed by thymic epithelial cells-TEC 11. In this respect, it is interesting to note the thymus as a target organ for other RNA viruses, such as HIV 12 and HTLV-1 13,14. In fact, we showed that cultured human TEC can be infected by HTLV-1 and convey virus particles to lymphoblastic T cells 15,16. We thus hypothesized that the thymic epithelium might also be infected by the Zika virus. Herein we provide compelling evidence that ZIKV targets human TEC both in vivo and in vitro. Data are provided showing that ZIKV-infection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, in vitro data revealed that the virus could modulate a high amount ...

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Section: Discussionsupporting

confidence: 93%

Zika virus targets the human thymic epithelium

Messias

Loss-Morais

Carvalho

et al. 2020

Sci Rep

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“…Initial studies using human retinal cells and new in vivo models, most commonly in rodents, are providing illuminating information in this regard. While this work is in its infancy, research from several groups has focused on the potential role of the human retinal pigment epithelial cell as a key cell in providing access to the eye, supporting DENV, ZIKV and EBOV replication and generating a strong innate anti‐viral response . Studies of infections induced in mice by local or systemic ZIKV inoculation demonstrate that, as well as retinal pigment epithelial cells, Mueller cells, also may be primary targets for these viruses .…”

Section: Resultsmentioning

confidence: 99%

“…While this work is in its infancy, research from several groups has focused on the potential role of the human retinal pigment epithelial cell as a key cell in providing access to the eye, supporting DENV, ZIKV and EBOV replication and generating a strong innate anti-viral response. [82][83][84] Studies of infections induced in mice by local or systemic ZIKV inoculation demonstrate that, as well as retinal pigment epithelial cells, Mueller cells, also may be primary targets for these viruses. 85,86 As these investigations expand, they may identify opportunities to develop novel anti-viral drugs targeted at key pathogenic viral and/or infected host cell molecules.…”

Section: Discussionmentioning

confidence: 99%

Emerging infectious uveitis: Chikungunya, dengue, Zika and Ebola: A review

Oliver

Carr

Smith

2019

Clinical Exper Ophthalmology

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Recently recognized forms of uveitis include intraocular inflammations that occur during or following one of several emerging infectious diseases: chikungunya fever, dengue, Zika virus disease and Ebola virus disease. Anterior, intermediate, posterior and pan‐uveitis have been described in individuals infected with chikungunya virus. Persons who contract dengue or Zika viruses also may develop different types of uveitis in the course of the infection: maculopathy is a common manifestation of dengue eye disease, and Zika eye disease may cause hypertensive anterior uveitis or mimic a white dot syndrome. Up to one‐third of Ebola survivors develop aggressive uveitis, which is frequently associated with vision loss and complicated by cataract. There are no specific anti‐viral drugs for these forms of uveitis, and thus treatment is largely supportive. In this article, we summarize the systemic infectious diseases and virology, and describe the clinical presentations, outcomes and management of emerging viral forms of uveitis.

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“…It has also been noted that flavivirus infection results in massive changes to the host/vector transcriptomes [38][39][40]. This may be the result of regulation of transcription, alternative splicing, or decay of transcripts.…”

Section: Alternative Functions Of Flavivirus Capsidsmentioning

confidence: 99%

“…The result of these interactions can result in either the activation or repression of various pathways with deleterious effects, including apoptosis or cell cycle arrest [19,37]. In addition, host transcriptome-wide profiles have been generated for various flaviviral infections in different cell types, indicating broad gene-level changes [38][39][40]. As capsid is one of the few viral proteins released from the ER membrane and has been shown to leave the replication compartments and enter the nucleus, it is reasonable to consider that it may be at least partially responsible for changes to the host transcriptome.…”

Section: Introductionmentioning

confidence: 99%

Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg

Sotcheff

Routh

2020

Pathogens

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Flaviviruses are enveloped positive-sense single-stranded RNA arboviruses, infectious to humans and many other animals and are transmitted primarily via tick or mosquito vectors. Capsid is the primary structural protein to interact with viral genome within virus particles and is therefore necessary for efficient packaging. However, in cells, capsid interacts with many proteins and nucleic acids and we are only beginning to understand the broad range of functions of flaviviral capsids. It is known that capsid dimers interact with the membrane of lipid droplets, aiding in both viral packaging and storage of capsid prior to packaging. However, capsid dimers can bind a range of nucleic acid templates in vitro, and likely interact with a range of targets during the flavivirus lifecycle. Capsid may interact with host RNAs, resulting in altered RNA splicing and RNA transcription. Capsid may also bind short interfering-RNAs and has been proposed to sequester these species to protect flaviviruses from the invertebrate siRNA pathways. Capsid can also be found in the nucleolus, where it wreaks havoc on ribosome biogenesis. Here we review flavivirus capsid structure, nucleic acid interactions and how these give rise to multiple functions. We also discuss how these features might be exploited either in the design of effective antivirals or novel vaccine strategies.

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Determination of system level alterations in host transcriptome due to Zika virus (ZIKV) Infection in retinal pigment epithelium

Cited by 40 publications

References 68 publications

Zika virus targets the human thymic epithelium

Zika virus targets the human thymic epithelium

Emerging infectious uveitis: Chikungunya, dengue, Zika and Ebola: A review

Understanding Flavivirus Capsid Protein Functions: The Tip of the Iceberg

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