RIG‐I mediates nonsegmented negative‐sense RNA virus‐induced inflammatory immune responses of primary human astrocytes

Furr, Samantha R.; Moerdyk-Schauwecker, Megan; Grdzelishvili, Valery Z.; Marriott, Ian

doi:10.1002/glia.21034

Cited by 47 publications

(75 citation statements)

References 48 publications

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“…The involvement of (RLR) pathway in inflammatory cytokine production has been reported earlier in a few virus infection models such as astrocyte infection by vesicular stomatitis virus, neuronal infection by Japanese encephalitis virus, hepatic cell infection by HCV and endothelial cells infection by Dengue virus [45,46,47,48]. In CHIKV infected fibroblasts, the activation of RLR signalling pathway has been identified [49].…”

Section: Discussionmentioning

confidence: 91%

Induction of Cytopathogenicity in Human Glioblastoma Cells by Chikungunya Virus

et al. 2013

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Chikungunya virus (CHIKV), an arthritogenic old-world alphavirus, has been implicated in the central nervous system (CNS) infection in infants and elderly patients. Astrocytes are the major immune cells of the brain parenchyma that mediate inflammation. In the present study we found that a local isolate of CHIKV infect and activate U-87 MG cells, a glioblastoma cell line of human astrocyte origin. The infection kinetics were similar in infected U-87 MG cells and the human embryo kidney (HEK293) cells as indicated by immunofluorescence and plaque assays, 24h post-infection (p.i.). In infected U-87 MG cells, apoptosis was detectable from 48h p.i. evidenced by DNA fragmentation, PARP cleavage, loss of mitochondrial membrane potential, nuclear condensation and visible cytopathic effects in a dose and time-dependent manner. XBP1 mRNA splicing and eIF2α phosphorylation studies indicated the occurrence of endoplasmic reticulum stress in infected cells. In U-87 MG cells stably expressing a green fluorescent protein-tagged light chain-3 (GFP-LC3) protein, CHIKV infection showed increased autophagy response. The infection led to an enhanced expression of the mRNA transcripts of the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CXCL9 within 24h p.i. Significant up-regulation of the proteins of RIG-I like receptor (RLR) pathway, such as RIG-I and TRAF-6, was observed indicating the activation of the cytoplasmic-cellular innate immune response. The overall results show that the U-87 MG cell line is a potential in vitro model for in depth study of these molecular pathways in response to CHIKV infection. The responses in these cells of CNS origin, which are inherently defective in Type I interferon response, could be analogous to that occurring in infants and very old patients who also have a compromised interferon-response. The results also point to the intriguing possibility of using this virus for studies to develop oncolytic virus therapy approaches against glioblastoma, a highly aggressive malignancy.

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Section: Discussionmentioning

confidence: 91%

Induction of Cytopathogenicity in Human Glioblastoma Cells by Chikungunya Virus

et al. 2013

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“…As such, these cells are ideally situated to detect and respond to invading pathogens including neurotropic viruses. Importantly, we have documented that microglia and astrocytes can be productively infected by VSV and respond by producing IL-6, TNF-α, and IL-1β(Chauhan et al, 2010; Furr et al, 2011, 2010), while earlier studies have demonstrated that these glial cells respond to VSV by proliferating, producing inducible NO synthase, and increasing the cell surface expression of MHC class II molecules (Bi et al, 1995), responses that are likely to set the stage for subsequent inflammatory damage.…”

Section: Neurotropism Of Vsvmentioning

confidence: 99%

Understanding and altering cell tropism of vesicular stomatitis virus

Hastie¹,

Cataldi²,

Marriott³

et al. 2013

Virus Research

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109

116

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Vesicular stomatitis virus (VSV) is a prototypic nonsegmented negative-strand RNA virus. VSV’s broad cell tropism makes it a popular model virus for many basic research applications. In addition, a lack of preexisting human immunity against VSV, inherent oncotropism and other features make VSV a widely used platform for vaccine and oncolytic vectors. However, VSV’s neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe vector. Therefore, it is very important to understand the determinants of VSV tropism and develop strategies to alter it. VSV glycoprotein (G) and matrix (M) protein play major roles in its cell tropism. VSV G protein is responsible for VSV broad cell tropism and is often used for pseudotyping other viruses. VSV M affects cell tropism via evasion of antiviral responses, and M mutants can be used to limit cell tropism to cell types defective in interferon signaling. In addition, other VSV proteins and host proteins may function as determinants of VSV cell tropism. Various approaches have been successfully used to alter VSV tropism to benefit basic research and clinically relevant applications.

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“…PRR activation in astrocytes results in the expression of many immune mediators, including inflammatory cytokines and type I IFNs (12,13). During infection by pathoType I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection.…”

Section: Introductionmentioning

confidence: 99%