Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention
| Autor: | Ronald N. Harty, Yuliang Liu, John M. Dye, Xiaohong Liu, Jianhong Lu, Bruce D. Freedman, Ziying Han, Jonathan J. Madara, Gordon Ruthel, Allen B. Reitz, Wenbo Liu, Laura I. Prugar, Jay E. Wrobel, Andrew M Herbert |
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| Předmět: |
lcsh:Immunologic diseases. Allergy
ORAI1 Protein viruses Immunology Filoviridae medicine.disease_cause Microbiology Viral Matrix Proteins Virology Genetics medicine Animals Humans lcsh:QH301-705.5 Molecular Biology Vero Cells Virus Release Ebola virus Arenavirus Viral matrix protein biology ORAI1 HEK 293 cells Virion RNA virus biology.organism_classification 3. Good health HEK293 Cells lcsh:Biology (General) Parasitology Calcium Calcium Channels lcsh:RC581-607 HeLa Cells Research Article |
| Zdroj: | BASE-Bielefeld Academic Search Engine PLoS Pathogens PLoS Pathogens, Vol 11, Iss 10, p e1005220 (2015) |
| DOI: | 10.1371/journal.ppat.1005220 |
| Popis: | Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junín viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca2+ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1) and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms. Author Summary Filoviruses (Ebola and Marburg viruses) and arenaviruses (Lassa and Junín viruses) are high-priority pathogens that hijack host proteins and pathways to complete their replication cycles and spread from cell to cell. Here we provide genetic and pharmacological evidence to demonstrate that the host calcium channel protein Orai1 and ER calcium sensor protein STIM1 regulate efficient budding and spread of BSL-4 pathogens Ebola, Marburg, Lassa, and Junín viruses. Our findings are of broad significance as they provide new mechanistic insight into fundamental, immutable, and conserved mechanisms of hemorrhagic fever virus pathogenesis. Moreover, this strategy of targeting highly conserved host cellular protein(s) and mechanisms required by these viruses to complete their life cycle should elicit minimal drug resistance. |
| Databáze: | OpenAIRE |
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