Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments.

Michal Barski,David Bhella,Swetha Vijayakrishnan,Richard M Elliott,Ona K Miller,Benjamin Brennan,Ulrich Schwarz-Linek,Jane A Potter,James H Naismith

doi:10.7554/elife.29236

Michal Barski, David Bhella + Show 7 more

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https://doi.org/10.7554/elife.29236

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Abstract

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.

Highlights

Rift Valley fever phlebovirus (RVFV), of the genus Phlebovirus, is one of the most clinically significant members of the Phenuiviridae family, of the Bunyavirales order (Elliott and Brennan, 2014; Plyusnin et al, 2012; Adams et al, 2017)
RVFV is an arbovirus spread by many mosquito vector species as well as by exposure to infected tissues
Originally endemic to sub-Saharan Africa, RVFV has recently appeared in Madagascar, the Comoros and the Arabian Peninsula (Balkhy and Memish, 2003)

Summary

Introduction

Rift Valley fever phlebovirus (RVFV), of the genus Phlebovirus, is one of the most clinically significant members of the Phenuiviridae family, of the Bunyavirales order (Elliott and Brennan, 2014; Plyusnin et al, 2012; Adams et al, 2017). RVFV is an arbovirus spread by many mosquito vector species as well as by exposure to infected tissues. It causes recurring epidemics in livestock and humans (Ikegami and Makino, 2011). The most prominent effect of RVFV infection in ruminants is a high rate of abortions. Increasing spread of competent mosquito vector species due to climate change could facilitate emergence of this virus in new ecosystems, including Europe and the United States (Chevalier, 2013; Elliott, 2009; Golnar et al, 2014; Rolin et al, 2013). While an animal vaccine for RVFV exists, there is no treatment available for human use (Boshra et al, 2011; Lihoradova and Ikegami, 2014)

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