Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

Han, Julianna; Perez, Jasmine T.; Chen, Cindy; Li, Yan; Benitez, Asiel A.; Kandasamy, Matheswaran; Lee, Yoontae; Andrade, Jorge; tenOever, Benjamin R.; Manicassamy, Balaji

doi:10.1016/j.celrep.2018.03.045

Cited by 215 publications

(205 citation statements)

References 49 publications

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“…RNAi has enabled systematic exploration of host genes involved in virus replication and virulence, thereby allowing identification of novel drug targets (Radoshitzky et al, 2016). Since the last decade, a large number of genome-scale RNAi screens have been conducted, which identified cellular factors required for WNV (Krishnan et al, 2008), DENV (Morchang et al, 2017;Sessions et al, 2009), HIV-1 (Zhou et al, 2008), HCV Lupberger et al, 2015;Tai et al, 2009), IAV (Han et al, 2018;Karlas et al, 2010), JUNV (Lavanya et al, 2013), coronavirus (Staff, 2015), poxvirus (Kilcher et al, 2014), herpesvirus (Griffiths et al, 2013) and polyomavirus (Zhao and Imperiale, 2017) replication. siRNA screens reveal both proviral and antiviral cellular factors and therefore help in understanding the precise nature of virus-host interactions .…”

Section: Genome-wide Sirna Screens To Identify Cellular Factors Requimentioning

confidence: 99%

Role of MAPK/MNK1 signaling in virus replication

et al. 2018

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Viruses are obligate intracellular parasites; they heavily depend on the host cell machinery to effectively replicate and produce new progeny virus particles. Following viral infection, diverse cell signaling pathways are initiated by the cells, with the major goal of establishing an antiviral state. However, viruses have been shown to exploit cellular signaling pathways for their own effective replication. Genome-wide siRNA screens have also identified numerous host factors that either support (proviral) or inhibit (antiviral) virus replication. Some of the host factors might be dispensable for the host but may be critical for virus replication; therefore such cellular factors may serve as targets for development of antiviral therapeutics. Mitogen activated protein kinase (MAPK) is a major cell signaling pathway that is known to be activated by diverse group of viruses. MAPK interacting kinase 1 (MNK1) has been shown to regulate both cap-dependent and internal ribosomal entry sites (IRES)-mediated mRNA translation. In this review we have discuss the role of MAPK in virus replication, particularly the role of MNK1 in replication and translation of viral genome.

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Section: Genome-wide Sirna Screens To Identify Cellular Factors Requimentioning

confidence: 99%

Role of MAPK/MNK1 signaling in virus replication

et al. 2018

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“…Interestingly, further evidence exists in recent studies that utilized genome-wide siRNA knockdown or CRISPR/Cas9 knockout screens on the potential pro-viral roles of TRIMs (e.g. TRIM23) [181]. This study does not mark the first instance of TRIM23 being identified in a screen as a pro-viral factor as the NS5 component of yellow fever virus (YFV) was found to require K63-linked polyubiquitin from TRIM23 in order to interact with STAT2 and inhibit IFN-I signalling [182].…”

Section: Novel Pro-viral Roles Of Trims and Other E3 Ubiquitin Ligasesmentioning

confidence: 99%

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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“…5,7 On the contrary, several genome-wide screens have identified host factors essential for influenza virus replication. [8][9][10] As an alternative to the aforementioned pathogen-targeted antivirals, growing efforts are devoted to blocking or promoting host factors to fight influenza viruses. 11 By modulating host factors involved in viral replications, these host-targeted antiviral strategies may be less susceptible to strain variations and mutations as they do not exert a selective pressure on the target pathogen.…”

Section: Introductionmentioning

confidence: 99%

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Hu¹,

Chen²,

Fang³

et al. 2018

IJN

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BackgroundInfluenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application.MethodsIn this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs’ anti-influenza applicability.ResultsUsing PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater in vitro antiviral activity, improving the therapeutic index of diphyllin and bafilomycin by approximately 3 and 5-fold, respectively. In a mouse model of sublethal influenza challenge, treatment with diphyllin nanoparticles resulted in reduced body weight loss and viral titer in the lungs. In addition, following a lethal influenza viral challenge, diphyllin nanoparticle treatment conferred a survival advantage of 33%.ConclusionsThese results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.

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Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

Cited by 215 publications

References 49 publications

Role of MAPK/MNK1 signaling in virus replication

Role of MAPK/MNK1 signaling in virus replication

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

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