p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection

Zhu, Shuang; Luo, Huanle; Liu, Hua; Ha, Yonju; Mays, Elizabeth; Lawrence, Ryan E.; Winkelmann, E.; Barrett, Alan D.T.; Smith, Sylvia B.; Wang, Min; Wang, Tian; Zhang, Wenbo

doi:10.1016/j.antiviral.2017.07.012

Cited by 23 publications

(17 citation statements)

References 51 publications

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“…HCEC indicating the potential role of these PRRs in regulating innate inflammatory and antiviral responses to ZIKV infection. These results corroborate with previous reports in the literature showing ZIKV and other flaviviruses, including DENV, West Nile virus (WNV), and Yellow fever virus (YFV), evoke immune responses by modulating the expression of these PRRs in various ocular [33,53,67,68] and non-ocular cell types [19,49,51,52,69]. Because our prior study had demonstrated the role of TLR3 in regulating antiviral response in HCECs, [70] and ZIKV was found to induce TLR3 both at mRNA and protein level, we propose that TLR3 signaling might play a role in corneal innate defense.…”

Section: Discussionsupporting

confidence: 92%

Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Singh

Farr

et al. 2019

The Ocular Surface

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Purpose: Zika virus (ZIKV) has emerged as an important human pathogen causing ocular complications. There have been reports of the shedding of ZIKV in human as well as animal tears. In this study, we investigated the infectivity of ZIKV in corneal epithelial cells and their antiviral immune response. Methods: Primary human corneal epithelial cells (Pr. HCECs) and an immortalized cell line (HUCL) were infected with two different strains of ZIKV (PRVABC59 & BeH823339) or dengue virus (DENV, serotypes 1-4). Viral infectivity was assessed by immunostaining of viral antigen and plaque assay. qRT-PCR and immunoblot analyses were used to assess the expression of innate inflammatory and antiviral genes. Supplementation of recombinant ISG15 (rISG15) and gene silencing approaches were used to elucidate the role of ISG15 in corneal antiviral defense. Results: Pr. HCECs, but not the HUCL cells, were permissive to both ZIKV strains and specifically to DENV3 infection. ZIKV induced the expression of viral recognition receptors (TLR3, RIG-I, & MDA5), and genes involved in inflammatory (CXCL10& CCL5) and antiviral (IFNs, MX1, OAS2, ISG15) responses in Pr. HCECs. Furthermore, ZIKV infection caused Pr. HCECs cell death, as evidenced by TUNEL staining. Silencing of ISG15 increased ZIKV infectivity while supplementation with rISG15 reduced ZIKV infection by direct inactivation of ZIKV and inhibiting its entry. Conclusions: Our study demonstrates for the first time, that ZIKV virus can readily infect and replicate in Pr. HCECs. Therefore, ZIKV may persist in the cornea and pose the potential risk of transmission via corneal transplantation.

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Section: Discussionsupporting

confidence: 92%

Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Singh

Farr

et al. 2019

The Ocular Surface

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“…ZIKV infection of RPE, Muller glia and the retinal endothelial cells leads to an increase in the markers of innate immune response along with interferon and interferon stimulated gene response in a time dependent manner and causes chorioretinal atrophy, RPE mottling and cell death in in vitro as well as in vivo models [ 75 , 94 , 112 ]. ZIKV induces the expression of AXL in all the retinal cell types except the photoreceptor cells and the TAM receptor seems to be the dominant receptor used for the infection of the retinal cell types.…”

Section: Interaction With Blood-retinal Barrier (Brb)mentioning

confidence: 99%

“…They activate several intracellular pathways, including ERK, p38MAPK, NF-kB, STAT3 and ER stress, thereby influencing the differential expression of growth and inflammatory factors. The p38MAPK has been shown to be strongly controlling the expression of inflammatory pathways and has been proven to be highly potent during many viral infections, including ZIKV [ 112 ].…”

Section: Interaction With Blood-retinal Barrier (Brb)mentioning

confidence: 99%

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

Singh

Kumar

2018

Viruses

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Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies, has rejuvenated a significant interest in understanding the pathogenesis of flaviviruses, including ZIKV, in the eye. In this review, first, we summarize the current knowledge of the major flaviviruses (Dengue, West Nile, Yellow Fever, and Japanese Encephalitis) reported to cause ocular manifestations in humans with emphasis on recent ZIKV outbreaks. Second, being an immune privilege organ, the eye is protected from systemic infections by the presence of blood-retinal barriers (BRB). Hence, we discuss how flaviviruses modulate retinal innate response and breach the protective BRB to cause ocular or retinal pathology. Finally, we describe recently identified infection signatures of ZIKV and discuss whether these system biology-predicted genes or signaling pathways (e.g., cellular metabolism) could contribute to the pathogenesis of ocular manifestations and assist in the development of ocular antiviral therapies against ZIKV and other flaviviruses.

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“…The Asian lineage ZIKV FSS13025 strain (ZIKV-FSS13025) [56], ZIKV PRVABC59 (ZIKV-PRV) strain, and ZIKV Dakar strain 41525 (ZIKV-Dakar) were obtained from the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA) at the University of Texas Medical Branch (UTMB) and were amplified once or twice in Vero cells. For ZIKV--Dakar-MA, a NS4B G18R mutation was introduced into ZIKV-Dakar infectious clone based on a previous study [57].…”

Section: Virusesmentioning

confidence: 99%

Peli1 signaling blockade attenuates congenital zika syndrome

Luo

Wang

et al. 2020

PLoS Pathog

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Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.

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p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Müller cells following Zika virus infection

Cited by 23 publications

References 51 publications

Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Interferon-stimulated gene 15 (ISG15) restricts Zika virus replication in primary human corneal epithelial cells

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

Peli1 signaling blockade attenuates congenital zika syndrome

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