Nipah virus W protein harnesses nuclear 14-3-3 to inhibit NF-κB-induced proinflammatory response

AbstractNipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns. It is able to inhibit the host innate immune response. Since the NF-κB pathway plays a crucial role in the innate antiviral response as a major transcriptional regulator of inflammation, we postulated its implication in the still poorly understood NiV immunopathogenesis. We report here that NiV inhibits the canonical NF-κB pathway via its nonstructural W protein. Translocation of the W protein into the nucleus causes nuclear accumulation of the cellular scaffold protein 14-3-3 in both African green monkey and human cells infected by NiV. Excess of 14-3-3 in the nucleus was associated with a reduction of NF-κB p65 subunit phosphorylation and of its nuclear accumulation. Importantly, W-S449A substitution impairs the binding of the W protein to 14-3-3 and the subsequent suppression of NF-κB signaling, thus restoring the production of proinflammatory cytokines. Our data suggest that the W protein increases the steady-state level of 14-3-3 in the nucleus and consequently enhances 14-3-3-mediated negative feedback on the NF-κB pathway. These findings provide a mechanistic model of W-mediated disruption of the host inflammatory response, which could contribute to the high severity of NiV infection.

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Evaluation of the Nipah epidemic containment and multisectoral involvement in Kerala using an appropriate management framework

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20203019 ◽

2020 ◽

Vol 7 (7) ◽

pp. 2813

Author(s):

Asma A. Rahim ◽

Sujina C. Muthukutty ◽

Sabitha R. Jacob ◽

Rini Ravindran ◽

Jayakrishnan Thayyil ◽

...

Keyword(s):

Health Personnel ◽

Viral Infections ◽

Nipah Virus ◽

Disease Outbreaks ◽

State Level ◽

The State ◽

Contact Tracing ◽

Outbreak Response ◽

Management Framework ◽

The Government

Kozhikode district of North Kerala, India witnessed an outbreak of Nipah virus (NiV) in the month of May 2018. Two adjacent districts were affected leaving 17 patients dead out of the 19 confirmed. United Nations and WHO lauded the expeditious response of the state’s health system in the diagnosis and containment of the outbreak which was unprecedented. The authors being in the contact tracing and surveillance operation district team, had kept a record of timeline of events and actions at the state level, compiled the news clippings and tracked events. In the absence of an end‑of‑epidemic report for reference, these records served as a valuable tool for the present review. We used the Management science for health frame work tool (MSH framework) to evaluate the district and state coordinated actions which helped in curbing the outbreak. Though NiV outbreak in South India (2018) had similar epidemiological features to previous disease outbreaks, it stands out as the one to be detected and contained in a short span of time. As health personnel working in the government medical college of an affected district and directly involved in contact tracing operations and containment measures, exploring and sharing, what worked and how, in the context of multidisciplinary response and recovery attempts of the outbreak in the state may be beneficial to public health personnel and policy makers. This management framework may be replicated in the national and international context, particularly in South East Asian region under threat of emerging viral infections like COVID-19, lacking specific epidemic management frameworks for outbreak response and containment.

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Identification of the Nuclear Export Signal and STAT-Binding Domains of the Nipah Virus V Protein Reveals Mechanisms Underlying Interferon Evasion

Journal of Virology ◽

10.1128/jvi.78.10.5358-5367.2004 ◽

2004 ◽

Vol 78 (10) ◽

pp. 5358-5367 ◽

Cited By ~ 92

Author(s):

Jason J. Rodriguez ◽

Cristian D. Cruz ◽

Curt M. Horvath

Keyword(s):

Amino Acids ◽

Protein Interactions ◽

Nuclear Export ◽

Nipah Virus ◽

Nuclear Export Signal ◽

Hendra Virus ◽

Nuclear Accumulation ◽

V Protein ◽

Binding Domains ◽

Export Signal

ABSTRACT The V proteins of Nipah virus and Hendra virus have been demonstrated to bind to cellular STAT1 and STAT2 proteins to form high-molecular-weight complexes that inhibit interferon (IFN)-induced antiviral transcription by preventing STAT nuclear accumulation. Analysis of the Nipah virus V protein has revealed a region between amino acids 174 and 192 that functions as a CRM1-dependent nuclear export signal (NES). This peptide is sufficient to complement an export-defective human immunodeficiency virus Rev protein, and deletion and substitution mutagenesis revealed that this peptide is necessary for both V protein shuttling and cytoplasmic retention of STAT1 and STAT2 proteins. However, the NES is not required for V-dependent IFN signaling inhibition. IFN signaling is blocked primarily by interaction between Nipah virus V residues 100 to 160 and STAT1 residues 509 to 712. Interaction with STAT2 requires a larger Nipah virus V segment between amino acids 100 and 300, but deletion of residues 230 to 237 greatly reduced STAT2 coprecipitation. Further, V protein interactions with cellular STAT1 is a prerequisite for STAT2 binding, and sequential immunoprecipitations demonstrate that V, STAT1, and STAT2 can form a tripartite complex. These findings characterize essential regions for Henipavirus V proteins that represent potential targets for therapeutic intervention.

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A Type III Effector NleF from EHEC Inhibits Epithelial Inflammatory Cell Death by Targeting Caspase-4

BioMed Research International ◽

10.1155/2017/4101745 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Ting Song ◽

Kaiwu Li ◽

Wei Zhou ◽

Jing Zhou ◽

Yuan Jin ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Cell ◽

Gastrointestinal Disease ◽

Highly Pathogenic ◽

E Coli ◽

Caspase 1 ◽

T3ss Effector ◽

Inflammatory Caspases ◽

Epithelial Cell Death ◽

Host Inflammatory Response

EnterohemorrhagicE. coli(EHEC) is a highly pathogenic bacterial strain capable of inducing severe gastrointestinal disease. Here, we show that EHEC uses the T3SS effector NleF to counteract the host inflammatory response by dampening caspase-4-mediated inflammatory epithelial cell death and by preventing the production of IL-1β. The other two inflammatory caspases, caspase-1 and caspase-5, are not involved in EHEC ΔnleF-induced inflammatory cell death. We found that NleF not only interrupted the heterodimerization of caspase-4-p19 and caspase-4-p10, but also inhibited the interaction of caspase-1 and caspase-4. The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death.

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Evaluation of a Single-Dose Nucleoside-Modified Messenger RNA Vaccine Encoding Hendra Virus-Soluble Glycoprotein Against Lethal Nipah virus Challenge in Syrian Hamsters

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz553 ◽

2019 ◽

Vol 221 (Supplement_4) ◽

pp. S493-S498 ◽

Cited By ~ 3

Author(s):

Michael K Lo ◽

Jessica R Spengler ◽

Stephen R Welch ◽

Jessica R Harmon ◽

JoAnn D Coleman-McCray ◽

...

Keyword(s):

Single Dose ◽

Immune Responses ◽

Messenger Rna ◽

Nipah Virus ◽

Hendra Virus ◽

Highly Pathogenic ◽

Syrian Hamsters ◽

Virus Challenge ◽

Pathogenic Viruses ◽

Rna Vaccine

Abstract In the absence of approved vaccines and therapeutics for use in humans, Nipah virus (NiV) continues to cause fatal outbreaks of encephalitis and respiratory disease in Bangladesh and India on a near-annual basis. We determined that a single dose of a lipid nanoparticle nucleoside-modified messenger RNA vaccine encoding the soluble Hendra virus glycoprotein protected up to 70% of Syrian hamsters from lethal NiV challenge, despite animals having suboptimally primed immune responses before challenge. These data provide a foundation from which to optimize future messenger RNA vaccination studies against NiV and other highly pathogenic viruses.

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The C, V and W proteins of Nipah virus inhibit minigenome replication

Journal of General Virology ◽

10.1099/vir.0.83582-0 ◽

2008 ◽

Vol 89 (5) ◽

pp. 1300-1308 ◽

Cited By ~ 34

Author(s):

Katrina Sleeman ◽

Bettina Bankamp ◽

Kimberly B. Hummel ◽

Michael K. Lo ◽

William J. Bellini ◽

...

Keyword(s):

Measles Virus ◽

Sequence Similarity ◽

Nipah Virus ◽

Amino Acid Sequence Similarity ◽

Dependent Manner ◽

Highly Pathogenic ◽

C Protein ◽

P Gene ◽

Dose Dependent ◽

Cat Expression

Nipah virus (NiV) is a recently emergent, highly pathogenic, zoonotic paramyxovirus of the genus Henipavirus. Like the phosphoprotein (P) gene of other paramyxoviruses, the P gene of NiV is predicted to encode three additional proteins, C, V and W. When the C, V and W proteins of NiV were tested for their ability to inhibit expression of the chloramphenicol acetyltransferase (CAT) reporter gene in plasmid-based, minigenome replication assays, each protein inhibited CAT expression in a dose-dependent manner. The C, V and W proteins of NiV also inhibited expression of CAT from a measles virus (MV) minigenome, but not from a human parainfluenzavirus 3 (hPIV3) minigenome. Interestingly, the C and V proteins of MV, which have previously been shown to inhibit MV minigenome replication, also inhibited NiV minigenome replication; however, they were not able to inhibit hPIV3 minigenome replication. In contrast, the C protein of hPIV3 inhibited minigenome replication of hPIV3, NiV and MV. Although there is very limited amino acid sequence similarity between the C, V and W proteins within the paramyxoviruses, the heterotypic inhibition of replication suggests that these proteins may share functional properties.

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in silico Docking Analysis of Small Molecule Inhibitors from Nyctanthes arbor-tristis against Nipah Virus Infection

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2019.ajomc-p235 ◽

2019 ◽

Vol 4 (4) ◽

pp. 244-247

Author(s):

Nayana Mohan ◽

V. Meera ◽

J. Soja ◽

M.S. Latha

Keyword(s):

Virus Infection ◽

Early Stage ◽

Nipah Virus ◽

Docking Simulation ◽

Severe Illness ◽

Highly Pathogenic ◽

Docking Analysis ◽

Computational Docking ◽

In Silico Docking ◽

Biosafety Level

Nipah virus is a highly pathogenic paramyxovirus belonging to the genus Henipavirus, classified as Biosafety Level 4 (BSL4) agents. The virus causes severe illness characterized by encephalitis or respiratory disease in human. The case-lethality rate of Nipah was reported to be 70 % in India, since year 2001. Despite the high pathogenicity of virus, no therapeutics are currently approved for use in human. But, ribavirin, favipiravir and human mono clonal antibody was found to reduce the intensity in early stage. Medicinal plants serve as a rich source of therapeutically active compounds. Nyctanthus arbortristis Linn or pavizhamalli (Harsinger) is traditionally known to have activity against Nipha virus. In this study, therapeutic activity of phytochemicals arbortristoside A and arbortristoside C present in pavizhamalli plant against Nipha virus target was investigated by computational docking simulation. Computational docking analysis was performed using Schrodinger Suite. The phytochemicals arbortristoside A and arbortristoside C show promising binding affinity with the target Nipah virus than the reference drugs. Results of the study could be advantageous to develop a new lead molecule against Nipah virus infection.

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Heparan Sulfate-Dependent Enhancement of Henipavirus Infection

mBio ◽

10.1128/mbio.02427-14 ◽

2015 ◽

Vol 6 (2) ◽

Cited By ~ 11

Author(s):

Cyrille Mathieu ◽

Kévin P. Dhondt ◽

Marie Châlons ◽

Stéphane Mély ◽

Hervé Raoul ◽

...

Keyword(s):

Heparan Sulfate ◽

Anticoagulant Activity ◽

Antiviral Treatment ◽

Mammalian Species ◽

Nipah Virus ◽

Hendra Virus ◽

Host Cells ◽

Emerging Infections ◽

Highly Pathogenic

ABSTRACTNipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genusHenipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirustrans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediatedtrans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cellsin vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections.IMPORTANCETheHenipavirusgenus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediatedtrans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cellsin vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.

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TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis

Infection and Immunity ◽

10.1128/iai.00440-15 ◽

2015 ◽

Vol 83 (8) ◽

pp. 3293-3301 ◽

Cited By ~ 13

Author(s):

Chao Yang ◽

Bo Chen ◽

Jianqing Zhao ◽

Lan Lin ◽

Li Han ◽

...

Keyword(s):

Mortality Rate ◽

Opposite Effect ◽

Early Stage ◽

Streptococcus Suis ◽

Innate Immune ◽

Proinflammatory Response ◽

Highly Pathogenic ◽

Content Type ◽

Pathogen Clearance

Infection with highly pathogenicStreptococcus suiscan cause septic shock, which is characterized by high levels of inflammatory cytokines and a high mortality rate. Our previous study indicated that TREM-1 (triggering receptor expressed on myeloid cells 1) was upregulated in swine spleen cells in response toS. suisinfection. The role of TREM-1 signaling in enhancement of the proinflammatory response promoted us to examine its effect on the outcome ofS. suisinfection. In the present study, the recombinant extracellular domain of TREM-1 (rTREM-1) and an agonistic TREM-1 antibody were used to inhibit and activate TREM-1 signaling to evaluate its role in neutrophil activation, pathogen clearance, proinflammatory cytokine response, and the outcome of highly pathogenicS. suisinfection in a mouse model. Blockage of TREM-1 signaling caused a more severe proinflammatory response toS. suisinfection and increased the mortality rate, while its activation had the opposite effect. Blockage or activation of TREM-1 signaling lowered or raised the number of neutrophils in the blood, which correlated well with host clearance ofS. suis. In conclusion, the TREM-1-mediated innate immune response played an essential role in the activation of neutrophils andS. suisclearance, which further reduced severe inflammation and finally benefited the outcome of the infection.

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ChAdOx1 NiV vaccination protects against lethal Nipah Bangladesh virus infection in African green monkeys

10.1101/2021.07.20.452991 ◽

2021 ◽

Author(s):

Neeltje van Doremalen ◽

Victoria Avanzato ◽

Friederike Feldmann ◽

Jonathan Schulz ◽

Elaine Haddock ◽

...

Keyword(s):

Cellular Response ◽

Nipah Virus ◽

Post Inoculation ◽

Lethal Challenge ◽

Highly Pathogenic ◽

Challenge Control ◽

Emerging Virus ◽

Severe Infections ◽

Humoral And Cellular Response ◽

Green Monkeys

Nipah virus (NiV) is a highly pathogenic and re-emerging virus which causes sporadic but severe infections in humans. Currently, no vaccines against NiV have been approved. We previously showed that ChAdOx1 NiV provides full protection against a lethal challenge with NiV Bangladesh (NiV-B) in hamsters. Here, we investigated the efficacy of ChAdOx1 NiV in the lethal African green monkeys (AGMs) NiV challenge model. AGMs were vaccinated either 4 weeks before challenge (prime vaccination), or 8 and 4 weeks before challenge with ChAdOx1 NiV (prime-boost vaccination). A robust humoral and cellular response was detected starting 14 days post initial vaccination. Upon challenge, control animals displayed a variety of signs and had to be euthanized between 5- and 7-days post inoculation. In contrast, vaccinated animals showed no signs of disease, and we were unable to detect infectious virus in all but one swab and all tissues. Importantly, no to limited antibodies against fusion protein or nucleoprotein IgG could be detected 42 days post challenge, suggesting that vaccination induced a very robust protective immune response preventing extensive virus replication.

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