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  • Review Article
  • Published:

Orthobunyaviruses: recent genetic and structural insights

Nature Reviews Microbiology volume 12, pages 673–685 (2014)Cite this article

Subjects

Key Points

  • Orthobunyaviruses are arthropod-transmitted viruses that are characterized by a tripartite, negative-sense RNA genome. Some viruses in this family are associated with diseases in humans (such as fever and encephalitis) and domesticated animals (including abortion and teratogenic effects in offspring). Schmallenberg virus, which is a recently emerged member of the family, caused a disease outbreak in domesticated animals in Europe in 2012–2013.

  • Viral replication occurs in the cytoplasm of infected cells and viruses mature by budding in the Golgi complex. Although infection of mammalian cells usually results in cell death, replication in arthropod vector cells is not cytopathic and these cells become persistently infected.

  • Viral mRNA synthesis is primed by capped oligonucleotides that are derived from host cell mRNAs in a process that is known as cap snatching. The endonuclease activity that is responsible for generating the primers is contained in the amino-terminal domain of the viral RNA-dependent RNA polymerase protein.

  • The three-dimensional structure of the viral N (nucleocapsid) protein shows that it forms a tetramer that contains a novel fold with a central, positively charged groove that binds to the viral RNA.

  • The viral non-structural protein NSs is the major virulence factor and antagonizes the host innate immune response by causing global inhibition of RNA polymerase II-mediated transcription.

  • Possession of a segmented genome enables orthobunyaviruses to evolve rapidly by segment reassortment during mixed infections. Reassortment occurs widely in nature and reassortant viruses can have dramatically altered properties, such as increased virulence.

  • Little is known about the burden of orthobunyavirus disease and there is a need for improved global surveillance to monitor orthobunyavirus activity.

Abstract

Orthobunyaviruses, which have small, tripartite, negative-sense RNA genomes and structurally simple virions composed of just four proteins, can have devastating effects on human health and well-being, either by causing disease in humans or by causing disease in livestock and crops. In this Review, I describe the recent genetic and structural advances that have revealed important insights into the composition of orthobunyavirus virions, viral transcription and replication and viral interactions with the host innate immune response. Lastly, I highlight outstanding questions and areas of future research.

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Figure 1: The orthobunayvirus particle.
Figure 2: Coding strategy of the orthobunyavirus genome.
Figure 3: Structure of the orthobunyavirus N protein.
Figure 4: The orthobunyavirus replication cycle.

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Acknowledgements

Work in the author's laboratory is supported by a Wellcome Trust Senior Investigator Award. The author apologizes to colleagues whose work could not be cited owing to space limitations.

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  1. MRC–University of Glasgow Centre for Virus Research, 464 Bearsden Road, Glasgow, G61 1QH, UK

    Richard M. Elliott

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Glossary

Arthrogryposis

A congenital abnormality in which the limb joints are deformed and inflexible.

Hydranencephaly

A condition that arises during foetal development, in which the central cavity of the brain is missing and is replaced with cerebrospinal fluid.

Complement fixation

An immunological test to measure whether antibody–antigen complexes can deplete a known concentration of standard complement proteins and protect added red blood cells from lysis. For orthobunyaviruses, complement-fixing antibodies are elicited by the nucleocapsid protein and are used to define serogroups.

Neutralization

An immunological test to detect antibodies that bind to a virus and reduce its titre in an infectivity assay. For orthobunyaviruses, neutralizing antibodies are elicited by the viral glycoproteins and are used for the identification of specific viruses.

Haemagglutination inhibition

An immunological test to measure the ability of antibodies to block the agglutination of red blood cells by a virus. For orthobunyaviruses, the viral glycoproteins mediate haemagglutination, and antibodies to these proteins that inhibit haemagglutination are used to define serogroups.

Cryoelectron microscopy

A technique that preserves the native state of biological material in a frozen hydrated state, which is usually achieved by rapid freezing in liquid ethane. Specimens are examined in a transmission electron microscope at ultralow temperatures and can be visualized without the need for heavy-metal staining.

Subtomographic averaging

An electron microscopy technique to visualize structures in three dimensions (3D). The specimen stage is tilted at regular increments and a series of transmission electron images is taken, which are then processed to generate a high-resolution (up to 5 nm) 3D image.

Leaky ribosomal scanning

A mechanism by which internal AUG codons in an mRNA are used to initiate translation. Ribosomes occasionally skip the first AUG codon, which is often not in an optimal sequence context for initiation, and a downstream AUG is selected instead.

Cap snatching

A mechanism to prime viral mRNA synthesis. A viral endonuclease cleaves the 5′ ends of cellular mRNAs about 12–18 nucleotides after the 5′ 7-methylguanylate residue (the cap), and the resulting short oligonucleotides are used to initiate viral mRNA transcription.

Class II fusion domain

Proteins that contain this domain mediate the fusion of viral membranes to cellular membranes. Class II fusion peptides, which are also known as betapenetrenes, are found internally in the surface glycoproteins of bunyaviruses, alphaviruses and flaviviruses and mostly comprise of β-structures.

Minigenome

A genome analogue that comprises the 3′ and 5′ UTRs of a viral genome segment and contains a reporter gene (for example, luciferase) in the negative-sense in place of the viral coding sequence.

DC-SIGN

(Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin). A calcium-dependent carbohydrate-binding protein (C-type lectin) receptor that is present on the surface of both macrophages and dendritic cells.

Macropinocytosis

A process that involves the uptake of molecules into cells in a clathrin-independent manner. Membrane ruffles trap fluid as they fold over themselves at the cell surface and undergo fusion, which results in vesicles that pinch off the membrane surface and hence deliver cargo to the cytoplasm.

Caveolar endocytosis

A clathrin-independent mechanism of endocytosis. Entry into cells is mediated by caveolae, which are flask-shaped invaginations on the cell surface that contain the protein caveolin.

Rabbit reticulocyte lysate

An in vitro or cell-free translation system that is based on nuclease-treated lysates of reticulocytes (the cells that are responsible for the production of haemoglobin), which enables the translation of exogenous RNAs.

Virus factory

A region of the host cell that is modified by the virus, such that it recruits cellular organelles and functions as a scaffold for virus assembly.

Endoglycosidase H

(Endo H). An enzyme that cleaves asparagine-linked high-mannose glycans from glycoproteins but does not digest complex oligosaccharide side chains. EndoH sensitivity is used as a marker to monitor oligosaccharide processing of a protein as it transits through the Golgi complex.

Exocytic pathway

The exocytic pathway consists of a series of membrane-bound organelles that transport proteins and lipids in vesicles from the ER to the cell surface.

RNAi

In the context of this Review, a gene-silencing mechanism in which viral RNAs are targeted for destruction by specific small interfering RNA molecules.

Pattern recognition receptors

(PRRs). A diverse group of membrane and cytoplasmic proteins that identify various microbial pathogen components to trigger the innate immune system.

Mediator

A multiprotein complex that functions as a key component of the RNA polymerase II transcriptional machinery. It functions as a bridge between the enzyme and regulatory proteins and is involved in both activation and repression of mRNA production.

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Elliott, R. Orthobunyaviruses: recent genetic and structural insights. Nat Rev Microbiol 12, 673–685 (2014). https://doi.org/10.1038/nrmicro3332

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