Key Points
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The new genus Henipavirus was created within the Paramyxovirinae subfamily of the Paramyxoviridae for the Biosafety Level 4 (BSL4) pathogens Hendra virus and Nipah virus. Both are highly pathogenic paramyxoviruses that have recently emerged from flying foxes to cause serious disease outbreaks in humans and livestock in Australia, Malaysia, Singapore and Bangladesh.
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Although they belong to the Paramyxovirinae subfamily, henipaviruses have distinct genetic and biological properties that distinguish them from other viruses in the subfamily, including respiroviruses such as Sendai virus, rubulaviruses such as mumps virus, and morbilliviruses such as measles virus.
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Research on the henipaviruses has been restricted by their BSL4 categorization; however, recent results mainly obtained using henipavirus proteins expressed from cloned genes have increased our understanding of the unique properties of particular henipavirus proteins, particularly the attachment (G) protein, the fusion (F) protein and the phosphoprotein (P) gene products.
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Among the features that distinguish the henipaviruses from other paramyxoviruses is their extraordinarily broad host range — they naturally infect flying foxes, horses, pigs, cats, dogs and humans — and the systemic infections that they cause, displaying a tropism for arterial rather than venous endothelial cells. The recent identification of the membrane receptor for the henipavirus G protein could explain these observations. The G protein of both HeV and NiV binds to ephrin B2, a conserved cell-surface glycoprotein that is widely distributed in vertebrates and is located preferentially in arterial endothelial cells and the surrounding tunica media, but is not found in venous endothelial cells. Ephrin B2 is also found in neurons, providing an explanation for virus growth in brain tissue and the occurrence of encephalitis in human patients.
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The F protein is a type I membrane protein, and a biologically active form of the F protein is generated by the proteolytic cleavage of a protein precursor. It was recently found that the henipavirus F protein is cleaved by the endosomal protease cathepsin L, at a cleavage site that is unique among viral glycoproteins. The widespread distribution of the cathepsin L might also be crucial in the systemic spread of virus and the transmission of infectious virus within and between species.
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The paramyxovirus P gene encodes three transcripts: the P, V and W proteins, each of which has a unique C-terminal domain and, compared with morbilliviruses and rubulaviruses, an N-terminal extension of 100–200 amino acids. P-gene products allow henipaviruses to evade host antiviral defences by inhibiting both dsRNA signalling and interferon (IFN) signalling. Both the V and W proteins inhibit dsRNA signalling, but their distinct C-terminal domains enable them to do so in different cellular compartments; the W protein contains a nuclear-localization signal in the C-terminal domain. The P, V and W proteins also inhibit IFN signalling by targeting the STAT proteins in a novel strategy for paramyxoviruses that involves STATs being sequestered in high-molecular-weight complexes and, again, the W protein acts in the nucleus.
Abstract
Hendra virus and Nipah virus are highly pathogenic paramyxoviruses that have recently emerged from flying foxes to cause serious disease outbreaks in humans and livestock in Australia, Malaysia, Singapore and Bangladesh. Their unique genetic constitution, high virulence and wide host range set them apart from other paramyxoviruses. These features led to their classification into the new genus Henipavirus within the family Paramyxoviridae and to their designation as Biosafety Level 4 pathogens. This review provides an overview of henipaviruses and the types of infection they cause, and describes how studies on the structure and function of henipavirus proteins expressed from cloned genes have provided insights into the unique biological properties of these emerging human pathogens.
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Acknowledgements
We thank A. Hyatt, F. Filippi and I. Pritchard for help with figures. B.T.E. and L.F.W. were supported in part by the Australian Biosecurity Cooperative Research Centre for emerging infectious diseases and the NIH/NSF 'Ecology of Infectious Diseases' award from the John E. Fogarty International Center. C.C.B. was supported by NIH grants to the Middle Atlantic Regional Center of Excellence for Biodefense and Emerging Infectious Disease.
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Glossary
- Zoonotic
-
A zoonotic infection is an infection of animals that can be transmitted to humans.
- Biosafety Level 4
-
(BSL4). BSL4 is the highest safety rating for laboratories, used for handling agents that pose a high risk of life-threatening disease and for which there is no vaccine or therapy. Other BSL4 agents include Ebola virus and Marburg virus.
- Type II membrane glycoproteins
-
Transmembrane glycoproteins with a cytoplasmic N terminus.
- Fc region
-
The region of an antibody that is responsible for binding to antibody receptors (FcR) on cells and the C1q component of complement.
- Tunica media
-
All blood vessels, except capillaries, comprise three layers surrounding a central lumen: the outer tunica adventitia, the inner tunica intima and the middle tunica media. The tunica media is composed predominantly of smooth muscle and also contains autonomic nerves.
- Type I membrane protein
-
A single-pass transmembrane protein that contains an N-terminal lumenal domain with carbohydrate moieties and a C-terminal cytoplasmic domain.
- trans-Golgi network
-
The area of the Golgi where secretory and membrane proteins are sorted to their final destination.
- Clathrin
-
A structural protein that polymerizes into polyhedral lattices to form a membrane coat around vesicles involved in membrane transport in both the endocytic and biosynthetic pathways.
- Nuclear-localization signal
-
A positively charged region of a protein that is responsible for directing its transport through nuclear-membrane pores and into the nucleus.
- Proteasomes
-
Most of the degradation of cytosolic and nuclear proteins in eukaryotic cells is catalysed by multi-subunit proteases known as proteasomes. Targeting of proteins to proteasomes most often occurs through the attachment of multiple ubiquitin tags.
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Eaton, B., Broder, C., Middleton, D. et al. Hendra and Nipah viruses: different and dangerous. Nat Rev Microbiol 4, 23–35 (2006). https://doi.org/10.1038/nrmicro1323
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DOI: https://doi.org/10.1038/nrmicro1323
