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Zentrale Tel.: 06221-560
Molekulare Virologie

AG Ruggieri

Alessia Ruggieri
Impact of virus-induced oscillating stress response on host cell

homeostasis and immune response induction

 


Phone: +49 (0)6221-56 7761

E-Mail: Alessia.Ruggieri@med.uni-heidelberg.de

 

 

 


Research Team Members


Kopp, KatjaKlein, PhilippMagg, VeraWelsch, Julia

 

 

Research Interests


Accumulation of viral products such as RNA replication intermediates and viral proteins represents a potent stressor for host cells. Rapidly after detection, host cells respond by implementing multiple defense mechanisms, including innate immune and stress responses. The strongest response to several forms of stress, including viral infections, is a global reduction of protein synthesis which promotes cellular survival by limiting the consumption of energy and nutrients. Translation suppression is induced by the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor-2 (eIF2α), which delivers initiator tRNAiMet to the small 40S ribosomal subunit, and thereby causes stalling of translation initiation. Among the four mammalian eIF2α kinases, protein kinase R (PKR) responds to double-stranded (ds) RNA in the cytoplasm and mediates an almost immediate translation inhibition upon replication of many RNA viruses. Global reduction of protein synthesis is intimately linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation pre-initiation complexes. By keeping pre-initiation complexes assembled, SGs are also thought to facilitate reactivation of translation when cells recover from stressful conditions. However, under conditions of sustained stress, recovery can fail and stress-related apoptosis can be activated. A number of viruses appear to antagonize SG formation during infection, while others may exploit SG responses for their replication.


In the last years, we addressed how chronic infections such as those caused by the hepatitis C virus (HCV) modulate cellular stress response to allow long-term viral replication and cell survival (see Ruggieri et al., Cell Host and Microbe 2012). Using long term live-cell imaging microscopy, we showed that HCV infection in combination with type 1 interferon (IFN) treatment induces a dynamic and oscillating host cell stress response that can be visualized by cycles of assembly/disassembly of SGs, concomitant with phases of active and stalled translation. This oscillating stress response is controlled by the antagonistic action of PKR, which senses dsRNA and phosphorylates eIF2α and DNA-damage-inducible 34, a regulatory subunit of protein phosphatase 1, which allows a rapid dephosphorylation of eIF2α and rapid reactivation of translation. Cycles are repeated as long as dsRNA persists in cells. Importantly, we showed that oscillating stress response is a conserved host cell reaction to infection with multiple single-stranded RNA viruses and a general mechanism to prevent long-lasting translation repression. However, negative-strand RNA viruses induce SGs that oscillate faster than those induced by HCV, likely due to differences in their replication strategy. In the case of cells infected with HCV in presence of IFN-α, these SG oscillations prolong cell survival by avoiding extended phases of protein synthesis shut-off. This implies that the balance between host cell stress response and virus replication facilitates HCV persistence and suggests that HCV may exploit the cellular stress response to establish persistence.

We are interested in understanding how viruses modulate SG formation to establish fine-tuned balance between host translation repressions, efficient virus genome translation and maintenance of host homeostasis, thereby allowing virus spread and survival. To provide a comprehensive and dynamic picture of this balance and further understand the complexity of SG biology in response to virus infection, we use a multi-disciplinary approach that combines classical techniques of cell biology, biochemistry and virology with live-cell imaging microscopy, as well as mathematical modeling.

 

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