Cells fight back against virus factories

Rabies virus stress granules This week I’ve been talking to first year students about cell biology, discussing how much the environment of the cell varies from one site to another within the cell. Viruses “know” this and much virus replication is localized at particular sites within the cell, not just occurring haphazardly. The first example of this is to be discioved were Negri bodies, the virus factories induced in rabies virus-infected cells. But how does the cell respond?

Exposure of cells to environmental stresses, such as heat shock and viral infection, induces a cellular response leading to the formation of Stress Granules composed of stalled translation initiation complexes (RNA-binding proteins and mRNA). Subsequent inhibition of host translation contibutes to cell survival. Viruses modulate or interfere with Stress Granule formation to control virus replication and antiviral responses, but differences exist in the dynamics and outcome of the stress responses induced by various viruses. A new paper shows that Rabies virus (RABV) induces the formation of Stress Granules in infected cells. Stress Granules are highly dynamic structures that increase in size by fusion events, exhibit transient assembly or persist throughout infection. They localize close to viral factories, cytoplasmic structures characteristic of RABV infection involved in viral replication and transcription. Viral messenger RNAs, but not viral genomic RNA, are transported from the factories to Stress Granules, indicating the communication between both compartments. RABV-induced cellular stress is dependent on double-stranded RNA-activated protein kinase (PKR). PKR also participates in innate immune responses through the induction of the Interferon-B gene. These results give an insight on new and important aspects of RABV infection and host antiviral stress responses.

 

Rabies Virus Infection Induces the Formation of Stress Granules Closely Connected to the Viral Factories. (2016) PLoS Pathog 12(10): e1005942. doi: 10.1371/journal.ppat.1005942
Stress granules (SGs) are membrane-less dynamic structures consisting of mRNA and protein aggregates that form rapidly in response to a wide range of environmental cellular stresses and viral infections. They act as storage sites for translationally silenced mRNAs under stress conditions. During viral infection, SG formation results in the modulation of innate antiviral immune responses, and several viruses have the ability to either promote or prevent SG assembly. Here, we show that rabies virus (RABV) induces SG formation in infected cells, as revealed by the detection of SG-marker proteins Ras GTPase-activating protein-binding protein 1 (G3BP1), T-cell intracellular antigen 1 (TIA-1) and poly(A)-binding protein (PABP) in the RNA granules formed during viral infection. As shown by live cell imaging, RABV-induced SGs are highly dynamic structures that increase in number, grow in size by fusion events, and undergo assembly/disassembly cycles. Some SGs localize in close proximity to cytoplasmic viral factories, known as Negri bodies (NBs). Three dimensional reconstructions reveal that both structures remain distinct even when they are in close contact. In addition, viral mRNAs synthesized in NBs accumulate in the SGs during viral infection, revealing material exchange between both compartments. Although RABV-induced SG formation is not affected in MEFs lacking TIA-1, TIA-1 depletion promotes viral translation which results in an increase of viral replication indicating that TIA-1 has an antiviral effect. Inhibition of PKR expression significantly prevents RABV-SG formation and favors viral replication by increasing viral translation. This is correlated with a drastic inhibition of IFN-B gene expression indicating that SGs likely mediate an antiviral response which is however not sufficient to fully counteract RABV infection.

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