In-Depth Assessment of an Outbreak of Nipah Encephalitis with Person-to-Person Transmission in Bangladesh: Implications for Prevention and Control Strategies

Blum, Lauren S.; Khan, Rasheda; Nahar, Nazmun; Breiman, Robert F.

doi:10.4269/ajtmh.2009.80.96

Cited by 80 publications

(91 citation statements)

References 15 publications

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“…In the past 2 years, examination of bats within and beyond the Pteropus genus has uncovered a multitude of previously undescribed henipaviruses of unknown virulence and implications for human health (4)(5)(6)(7). The more widespread prevalence of henipaviruses and the documented human-to-human transmission of some strains (8)(9)(10), along with recent evidence of potential henipavirus-like spillover events in Africa (11), suggest that increased global surveillance efforts directed at detecting henipavirus spillover events are warranted. Indeed, pandemic potential has been proposed for NiV (12).…”

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confidence: 99%

Efficient Reverse Genetics Reveals Genetic Determinants of Budding and Fusogenic Differences between Nipah and Hendra Viruses and Enables Real-Time Monitoring of Viral Spread in Small Animal Models of Henipavirus Infection

Yun

Park

Hill

et al. 2015

J Virol

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Nipah virus (NiV) and Hendra virus (HeV) are closely related henipaviruses of the Paramyxovirinae. Spillover from their fruit bat reservoirs can cause severe disease in humans and livestock. Despite their high sequence similarity, NiV and HeV exhibit apparent differences in receptor and tissue tropism, envelope-mediated fusogenicity, replicative fitness, and other pathophysiologic manifestations. To investigate the molecular basis for these differences, we first established a highly efficient reverse genetics system that increased rescue titers by >3 log units, which offset the difficulty of generating multiple recombinants under constraining biosafety level 4 (BSL-4) conditions. We then replaced, singly and in combination, the matrix (M), fusion (F), and attachment glycoprotein (G) genes in mCherry-expressing recombinant NiV (rNiV) with their HeV counterparts. These chimeric but isogenic rNiVs replicated well in primary human endothelial and neuronal cells, indicating efficient heterotypic complementation. The determinants of budding efficiency, fusogenicity, and replicative fitness were dissociable: HeV-M budded more efficiently than NiV-M, accounting for the higher replicative titers of HeV-M-bearing chimeras at early times, while the enhanced fusogenicity of NiV-G-bearing chimeras did not correlate with increased replicative fitness. Furthermore, to facilitate spatiotemporal studies on henipavirus pathogenesis, we generated a firefly luciferase-expressing NiV and monitored virus replication and spread in infected interferon alpha/beta receptor knockout mice via bioluminescence imaging. While intraperitoneal inoculation resulted in neuroinvasion following systemic spread and replication in the respiratory tract, intranasal inoculation resulted in confined spread to regions corresponding to olfactory bulbs and salivary glands before subsequent neuroinvasion. This optimized henipavirus reverse genetics system will facilitate future investigations into the growing numbers of novel henipaviruslike viruses. IMPORTANCENipah virus (NiV) and Hendra virus (HeV) are recently emergent zoonotic and highly lethal pathogens with pandemic potential. Although differences have been observed between NiV and HeV replication and pathogenesis, the molecular basis for these differences has not been examined. In this study, we established a highly efficient system to reverse engineer changes into replication-competent NiV and HeV, which facilitated the generation of reporter-expressing viruses and recombinant NiV-HeV chimeras with substitutions in the genes responsible for viral exit (the M gene, critical for assembly and budding) and viral entry (the G [attachment] and F [fusion] genes). These chimeras revealed differences in the budding and fusogenic properties of the M and G proteins, respectively, which help explain previously observed differences between NiV and HeV. Finally, to facilitate future in vivo studies, we monitored the replication and spread of a bioluminescent reporter-expressing NiV in susceptible mice; th...

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Efficient Reverse Genetics Reveals Genetic Determinants of Budding and Fusogenic Differences between Nipah and Hendra Viruses and Enables Real-Time Monitoring of Viral Spread in Small Animal Models of Henipavirus Infection

Yun

Park

Hill

et al. 2015

J Virol

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“…Zoonotic transfer of NiV to human populations from these natural reservoirs (5), sometimes through an animal intermediary such as pigs (6), leads to rapidonset encephalitis with case-fatality rates >90% (1). Following zoonosis, some cases of person-to-person transmission have been observed (7,8). Although bats are the predominant host reservoir, a putative henipa-like virus (HNLV), Mojiang virus (MojV), associated with severe pneumonia and three case fatalities, has also been isolated from rats in China (9).…”

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Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus

Lee

Pernet

Ahmed

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The discovery of African henipaviruses (HNVs) related to pathogenic Hendra virus (HeV) and Nipah virus (NiV) from Southeast Asia and Australia presents an open-ended health risk. Cell receptor use by emerging African HNVs at the stage of host-cell entry is a key parameter when considering the potential for spillover and infection of human populations. The attachment glycoprotein from a Ghanaian bat isolate (GhV-G) exhibits <30% sequence identity with Asiatic NiV-G/HeV-G. Here, through functional and structural analysis of GhV-G, we show how this African HNV targets the same human cell-surface receptor (ephrinB2) as the Asiatic HNVs. We first characterized this virus−receptor interaction crystallographically. Compared with extant HNV-G-ephrinB2 structures, there was significant structural variation in the six-bladed β-propeller scaffold of the GhV-G receptor-binding domain, but not the Greek key fold of the bound ephrinB2. Analysis revealed a surprisingly conserved mode of ephrinB2 interaction that reflects an ongoing evolutionary constraint among geographically distal and phylogenetically divergent HNVs to maintain the functionality of ephrinB2 recognition during virus-host entry. Interestingly, unlike NiV-G/HeV-G, we could not detect binding of GhV-G to ephrinB3. Comparative structurefunction analysis further revealed several distinguishing features of HNV-G function: a secondary ephrinB2 interaction site that contributes to more efficient ephrinB2-mediated entry in NiV-G relative to GhV-G and cognate residues at the very C terminus of GhV-G (absent in Asiatic HNV-Gs) that are vital for efficient receptorinduced fusion, but not receptor binding per se. These data provide molecular-level details for evaluating the likelihood of African HNVs to spill over into human populations.emerging virus | viral attachment | glycoprotein | henipavirus | structure

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“…Paramyxoviruses produce a polymerase-associated phosphoprotein (P) that is necessary for viral replication. Through an idiosyncratic editing property of the viral polymerase, nontemplated guanine residues are inserted into the P-gene mRNA, resulting in genomic diversification from these frameshift mutations (7,17,26,30,37,39,43). These additional gene products have been demonstrated to interfere with IFN signaling (48,59,60).…”

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Novel Nipah Virus Immune-Antagonism Strategy Revealed by Experimental and Computational Study

Seto

Qiao

Guenzel

et al. 2010

J Virol

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Nipah virus is an emerging pathogen that causes severe disease in humans. It expresses several antagonist proteins that subvert the immune response and that may contribute to its pathogenicity. Studies of its biology are difficult due to its high pathogenicity and requirement for biosafety level 4 containment. We integrated experimental and computational methods to elucidate the effects of Nipah virus immune antagonists. Individual Nipah virus immune antagonists (phosphoprotein and V and W proteins) were expressed from recombinant Newcastle disease viruses, and the responses of infected human monocyte-derived dendritic cells were determined. We developed an ordinary differential equation model of the infectious process that that produced results with a high degree of correlation with these experimental results. In order to simulate the effects of wild-type virus, the model was extended to incorporate published experimental data on the time trajectories of immune-antagonist production. These data showed that the RNA-editing mechanism utilized by the wild-type Nipah virus to produce immune antagonists leads to a delay in the production of the most effective immune antagonists, V and W. Model simulations indicated that this delay caused a disconnection between attenuation of the antiviral response and suppression of inflammation. While the antiviral cytokines were efficiently suppressed at early time points, some early inflammatory cytokine production occurred, which would be expected to increase vascular permeability and promote virus spread and pathogenesis. These results suggest that Nipah virus has evolved a unique immune-antagonist strategy that benefits from controlled expression of multiple antagonist proteins with various potencies.

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In-Depth Assessment of an Outbreak of Nipah Encephalitis with Person-to-Person Transmission in Bangladesh: Implications for Prevention and Control Strategies

Cited by 80 publications

References 15 publications

Efficient Reverse Genetics Reveals Genetic Determinants of Budding and Fusogenic Differences between Nipah and Hendra Viruses and Enables Real-Time Monitoring of Viral Spread in Small Animal Models of Henipavirus Infection

Efficient Reverse Genetics Reveals Genetic Determinants of Budding and Fusogenic Differences between Nipah and Hendra Viruses and Enables Real-Time Monitoring of Viral Spread in Small Animal Models of Henipavirus Infection

Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus

Novel Nipah Virus Immune-Antagonism Strategy Revealed by Experimental and Computational Study

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