Exploitation of Cytoskeletal Networks during Early Viral Infection

Walsh, Derek; Naghavi, Mojgan H.

doi:10.1016/j.tim.2018.06.008

Cited by 84 publications

(69 citation statements)

References 113 publications

(115 reference statements)

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“…Latent RNase L interaction with the actin cytoskeleton, namely the scaffolding protein Filamin A, inhibits viral entry, and this interaction is disrupted by activation of RNase L (48). In the context of ZIKV infection, a potential latent RNase L-cytoskeletal interaction could improve replication by aiding in RF formation rather than prevent it, consistent with other viruses that engage cytoskeletal components to enable viral life cycle events (49,50).…”

Section: Figmentioning

confidence: 89%

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Whelan

Silverman

et al. 2019

J Virol

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There is currently no knowledge of how the emerging human pathogen Zika virus (ZIKV) interacts with the antiviral endoribonuclease L (RNase L) pathway during infection. Since activation of RNase L during infection typically limits virus production dramatically, we used CRISPR-Cas9 gene editing technology to knockout (KO) targeted host genes involved in the RNase L pathway to evaluate the effects of RNase L on ZIKV infection in human A549 cells. RNase L was activated in response to ZIKV infection, which degraded ZIKV genomic RNA. Surprisingly, despite viral genome reduction, RNase L activity did not reduce ZIKV infectious titers. In contrast, both the flavivirus dengue virus and the alphavirus Sindbis virus replicated to significantly higher titers in RNase L KO cells compared to wild-type (WT) cells. Using MAVS/RNase L double KO cells, we demonstrated that the absence of increased ZIKV production in RNase L KO cells was not due to compensation by enhanced type I interferon transcripts to thus inhibit virus production. Finally, when synthetic doublestranded RNA was detected by OAS3 to induce RNase L antiviral activity prior to ZIKV infection, we observed reduced ZIKV replication factory formation, as well as a 42-fold reduction in virus yield in WT but not RNase L KO cells. This study proposes that ZIKV evades RNase L antiviral activity by generating a viral genome reservoir protected from RNase L cleavage during early infection, allowing for sufficient virus production before RNase L activation is detectable.

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Section: Figmentioning

confidence: 89%

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Whelan

Silverman

et al. 2019

J Virol

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“…Viruses are obligate intracellular parasites that require the involvement of the actin cytoskeleton at all stages, from entry through replication to egress and spread (Taylor et al, 2011). With a few exceptions of viruses that predominantly exploit actin-driven motility, most viruses switch from the actin cytoskeleton to the microtubule tracks to promote longrange movement of their cores (Walsh and Naghavi, 2019). The drug jasplakinolide, which binds to F-actin and results in a decreased rate of actin depolymerization, was previously used to block the turnover of actin microfilaments (Cramer, 1999).…”

Section: Role Of Actin Cytoskeleton and Microtubules In Zikv Infectiomentioning

confidence: 99%

Characterization of Zika Virus Endocytic Pathways in Human Glioblastoma Cells

Zhang

et al. 2020

Front. Microbiol.

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Zika virus (ZIKV) infections can cause microcephaly and neurological disorders. However, the early infection events of ZIKV in neural cells remain to be characterized. Here, by using a combination of pharmacological and molecular approaches and the human glioblastoma cell T98G as a model, we first observed that ZIKV infection was inhibited by chloroquine and NH 4 Cl, indicating a requirement of low intracellular pH. We further showed that dynamin is required as the ZIKV entry was affected by the specific inhibitor dynasore, small interfering RNA (siRNA) knockdown of dynamin, or by expressing the dominant-negative K44A mutant. Moreover, the ZIKV entry was significantly inhibited by chlorpromazine, pitstop2, or siRNA knockdown of clathrin heavy chain, indicating an involvement of clathrin-mediated endocytosis. In addition, genistein treatment, siRNA knockdown of caveolin-1, or overexpression of a dominantnegative caveolin mutant impacted the ZIKV entry, with ZIKV particles being observed to colocalize with caveolin-1, implying that caveola endocytosis can also be involved. Furthermore, we found that the endocytosis of ZIKV is dependent on membrane cholesterol, microtubules, and actin cytoskeleton. Importantly, ZIKV infection was inhibited by silencing of Rab5 and Rab7, while confocal microscopy showed that ZIKV particles localized in Rab5-and Rab7-postive endosomes. These results indicated that, after internalization, ZIKV likely moves to Rab5-positive early endosome and Rab7positive late endosomes before delivering its RNA into the cytoplasm. Taken together, our study, for the first time, described the early infection events of ZIKV in human glioblastoma cell T98G.

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“…We published the first demonstration of HIV (or any virus) requiring target cell actin-myosin cytoskeletal function for fusion-mediated entry, specifically, co-capping of CD4 and CKRs (36). Our results with cell-free virions were subsequently confirmed for cell-associated HIV (40,41), and for several other types of virus (59,85). Given the paucity of HIV envelope fusion spikes (<100 per virion), and the need for multiple trimeric spikes to simultaneously engage their receptors and insert envelope fusion components to efficiently mediate membrane penetration, we have argued that the use of a single cell surface receptor for virus places a much lower stochastic burden on binding than the requirement for simultaneous dual receptor binding.…”

mentioning

confidence: 61%

Recognition of Apoptotic Cells by Viruses and Cytolytic Lymphocytes: Target Selection in the Fog of War

Schwartz

Iyengar

2020

Viral Immunology

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Viruses and cytolytic lymphocytes operate in an environment filled with dying and dead cells, and cell fragments. For viruses, irreversible fusion with doomed cells is suicide. For cytotoxic T lymphocyte and natural killer cells, time and limited lytic resources spent on apoptotic targets is wasteful and may result in death of the host. We make the case that the target membrane cytoskeleton is the best source of information regarding the suitability of potential targets for engagement for both viruses and lytic effector cells, and we present experimental evidence for detection of apoptotic cells by HIV, without loss of infectivity.

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Exploitation of Cytoskeletal Networks during Early Viral Infection

Cited by 84 publications

References 113 publications

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Characterization of Zika Virus Endocytic Pathways in Human Glioblastoma Cells

Recognition of Apoptotic Cells by Viruses and Cytolytic Lymphocytes: Target Selection in the Fog of War

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