An Overview of Conventional and Black Cumin Seeds (Nigella sativa) Therapy in the Management of Nipah Viral Infection.

The recent outbreaks of Nipah viral infection were associated with severe respiratory illness, lethal encephalitis, and an extremely high mortality rate. As there are no approved antiviral medications, patients with NiV infections are currently treated with repurposed or investigational antivirals and supportive care. This review examines the potential health benefits of N. sativa in the treatment of NiV infection. To identify relevant studies, the literature was searched in online databases like Medline/PubMed, Google Scholar, Science Direct, and reference lists. Through its antiviral, anti-inflammatory, antioxidant, anticonvulsant, immunomodulatory, bronchodilatory, and other properties, a number of studies have demonstrated that N. sativa is effective against a variety of viral infections, inflammatory conditions, neurological and respiratory illnesses, and other conditions. As a result, in the treatment of NiV-infected patients, N. sativa could be added as an adjuvant treatment alongside repurposed or investigational antivirals and supportive care. The efficacy of N. sativa in the treatment of NiV infection will be determined by the results of upcoming randomized controlled clinical trials.

Overview of Experimental Vaccines and Antiviral Therapeutics for Henipavirus Infection.

Hendra virus (HeV) and Nipah virus (NiV) are highly pathogenic paramyxoviruses, which have emerged in recent decades and cause sporadic outbreaks of respiratory and encephalitic disease in Australia and Southeast Asia, respectively. Over two billion people currently live in regions potentially at risk due to the wide range of the Pteropus fruit bat reservoir, yet there are no approved vaccines or therapeutics to protect against or treat henipavirus disease. In recent years, significant progress has been made toward developing various experimental vaccine platforms and therapeutics. Here, we describe these advances for both human and livestock vaccine candidates and discuss the numerous preclinical studies and the few that have progressed to human phase 1 clinical trial and the one approved veterinary vaccine.

Late remdesivir treatment initiation partially protects African green monkeys from lethal Nipah virus infection.

Remdesivir is a nucleotide prodrug with preclinical efficacy against lethal Nipah virus infection in African green monkeys when administered 1 day post inoculation (dpi) (Lo et al., 2019). Here, we determined whether remdesivir treatment was still effective when treatment administration initiation was delayed until 3 dpi. Three groups of six African green monkeys were inoculated with a lethal dose of Nipah virus, genotype Bangladesh. On 3 dpi, one group received a loading dose of 10 mg/kg remdesivir followed by daily dosing with 5 mg/kg for 11 days, one group received 10 mg/kg on 12 consecutive days, and the remaining group received an equivalent volume of vehicle solution. Remdesivir treatment initiation on 3 dpi provided partial protection from severe Nipah virus disease that was dose dependent, with 67% of animals in the high dose group surviving the challenge. However, remdesivir treatment did not prevent clinical disease, and surviving animals showed histologic lesions in the brain. Thus, early administration seems critical for effective remdesivir treatment during Nipah virus infection.

Nipah Virus: An Updated Review and Emerging Challenges.

Many hospitals are teetering on the edge of being overwhelmed, with many already there because of the COVID-19 pandemic. Moreover, a recent report has also warned about the Nipah virus (NiV). NiV is a pleomorphic enveloped virus that belongs to the Paramyxoviridae family (genus Henipavirus); it affects both the respiratory and central nervous systems, with a fatality rate ranging from 40% to 75%, as documented by the World Health Organization. The first reported NiV outbreak was in early 1999 in Malaysia among people who contacted infected pigs. NiV also affected Bangladesh and India, where the main infection route was the consumption of raw date palm sap contaminated by bats. The World Health Organization has listed NiV as one of the emerging pathogens that can lead to severe outbreaks at any moment in the future with limited medical preparations and only a few projects in pharmaceutical firms. There is no licensed treatment for human use against NiV until now, and the management is limited to supportive care and symptomatic treatment. In severe cases with neurologic and respiratory complications, intensive care is needed. This article reviews the published literature and highlights the latest updates about this emerging pathogen and the methods to avoid the spread of this disease during this critical period.

Medical countermeasures against henipaviruses: a review and public health perspective.

Henipaviruses, including Nipah virus, are regarded as pathogens of notable epidemic potential because of their high pathogenicity and the paucity of specific medical countermeasures to control infections in humans. We review the evidence of medical countermeasures against henipaviruses and project their cost in a post-COVID-19 era. Given the sporadic and unpredictable nature of henipavirus outbreaks, innovative strategies will be needed to circumvent the infeasibility of traditional phase 3 clinical trial regulatory pathways. Stronger partnerships with scientific institutions and regulatory authorities in low-income and middle-income countries can inform coordination of appropriate investments and development of strategies and normative guidelines for the deployment and equitable use of multiple medical countermeasures. Accessible measures should include global, regional, and endemic in-country stockpiles of reasonably priced small molecules, monoclonal antibodies, and vaccines as part of a combined collection of products that could help to control henipavirus outbreaks and prevent future pandemics.

COVID-19, Ebola virus disease, and Nipah virus infection reclassification as novel acute immune dysrhythmia syndrome (n-AIDS): potential crucial role for immunomodulators.

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.

A recombinant Cedar virus based high-throughput screening assay for henipavirus antiviral discovery.

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic, bat-borne paramyxoviruses in the genus Henipavirus that cause severe and often fatal acute respiratory and/or neurologic diseases in humans and livestock. There are currently no approved antiviral therapeutics or vaccines for use in humans to treat or prevent NiV or HeV infection. To facilitate development of henipavirus antivirals, a high-throughput screening (HTS) platform was developed based on a well-characterized recombinant version of the nonpathogenic Henipavirus, Cedar virus (rCedV). Using reverse genetics, a rCedV encoding firefly luciferase (rCedV-Luc) was rescued and its utility evaluated for high-throughput antiviral compound screening. The luciferase reporter gene signal kinetics of rCedV-Luc in different human cell lines was characterized and validated as an authentic real-time measure of viral growth. The rCedV-Luc platform was optimized as an HTS assay that demonstrated high sensitivity with robust Z' scores, excellent signal-to-background ratios and coefficients of variation. Eight candidate compounds that inhibited rCedV replication were identified for additional validation and demonstrated that 4 compounds inhibited authentic NiV-Bangladesh replication. Further evaluation of 2 of the 4 validated compounds in a 9-point dose response titration demonstrated potent antiviral activity against NiV-Bangladesh and HeV, with minimal cytotoxicity. This rCedV reporter can serve as a surrogate yet authentic BSL-2 henipavirus platform that will dramatically accelerate drug candidate identification in the development of anti-henipavirus therapies.

Multi-step molecular docking and dynamics simulation-based screening of large antiviral specific chemical libraries for identification of Nipah virus glycoprotein inhibitors.

Nipah virus (NiV) infections are highly contagious and can cause severe febrile encephalitis. An outbreak of NiV infection has reported high mortality rates in Southeast Asian countries including Bangladesh, East Timor, Malaysia, Papua New Guinea, Vietnam, Cambodia, Indonesia, Madagascar, Philippines, Thailand and India. Considering the high risk for an epidemic outbreak, the World Health Organization (WHO) declared NiV as an emerging priority pathogen. However, there are no effective therapeutics or any FDA approved drugs available for the treatment of this infection. Among the known nine proteins of NiV, glycoprotein plays an important role in initiating the entry of viruses and attaching to the host cell receptors. Herein, three antiviral databases consisting of 79,892 chemical entities have been computationally screened against NiV glycoprotein (NiV-G). Particularly, multi-step molecular docking followed by extensive molecular binding interactions analyses, binding free energy estimation, in silico pharmacokinetics, synthetic accessibility and toxicity profile evaluations have been carried out for initial identification of potential NiV-G inhibitors. Further, molecular dynamics (MD) simulation has been performed to understand the dynamic properties of NiV-G protein-bound with proposed five inhibitors (G1-G5) and their interactions behavior, and any conformational changes in NiV-G protein during simulations. Moreover, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) based binding free energies (∆G) has been calculated from all MD simulation trajectories to understand the energy contribution of each proposed compound in maintaining and stabilizing the complex binding interactions with NiV-G protein. Proposed compounds showed high negative ∆G values ranging from -166.246 to -226.652 kJ/mol indicating a strong affinity towards the NiV-G protein.

Griffithsin Inhibits Nipah Virus Entry and Fusion and Can Protect Syrian Golden Hamsters From Lethal Nipah Virus Challenge.

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses, including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics.

NipahVR: a resource of multi-targeted putative therapeutics and epitopes for the Nipah virus.

Nipah virus (NiV) is an emerging and priority pathogen from the Paramyxoviridae family with a high fatality rate. It causes various diseases such as respiratory ailments and encephalitis and poses a great threat to humans and livestock. Despite various efforts, there is no approved antiviral treatment available. Therefore, to expedite and assist the research, we have developed an integrative resource NipahVR (http://bioinfo.imtech.res.in/manojk/nipahvr/) for the multi-targeted putative therapeutics and epitopes for NiV. It is structured into different sections, i.e. genomes, codon usage, phylogenomics, molecular diagnostic primers, therapeutics (siRNAs, sgRNAs, miRNAs) and vaccine epitopes (B-cell, CTL, MHC-I and -II binders). Most decisively, potentially efficient therapeutic regimens targeting different NiV proteins and genes were anticipated and projected. We hope this computational resource would be helpful in developing combating strategies against this deadly pathogen. Database URL: http://bioinfo.imtech.res.in/manojk/nipahvr/.

An antibody against the F glycoprotein inhibits Nipah and Hendra virus infections.

Nipah virus (NiV) and Hendra virus (HeV) are zoonotic henipaviruses (HNVs) responsible for outbreaks of encephalitis and respiratory illness with fatality rates of 50-100%. No vaccines or licensed therapeutics currently exist to protect humans against NiV or HeV. HNVs enter host cells by fusing the viral and cellular membranes via the concerted action of the attachment (G) and fusion (F) glycoproteins, the main targets of the humoral immune response. Here, we describe the isolation and humanization of a potent monoclonal antibody cross-neutralizing NiV and HeV. Cryo-electron microscopy, triggering and fusion studies show the antibody binds to a prefusion-specific quaternary epitope, conserved in NiV F and HeV F glycoproteins, and prevents membrane fusion and viral entry. This work supports the importance of the HNV prefusion F conformation for eliciting a robust immune response and paves the way for using this antibody for prophylaxis and post-exposure therapy with NiV- and HeV-infected individuals.

Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge.

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.

Progressive multifocal leukoencephalopathy in Zambia is caused by JC virus with prototype regulatory region.

There are only few documented cases of progressive multifocal leukoencephalopathy (PML) in Africa. Whether this is caused by a lack of JC virus (JCV) spread or alteration in the JCV genome is unknown. We characterized the clinical presentation, laboratory findings, and JCV regulatory region (RR) pattern of the first documented PML cases in Zambia as well as JCV seroprevalence among HIV+ and HIV- Zambians. We identified PML patients with positive JCV DNA PCR in their cerebrospinal fluid (CSF) among subjects enrolled in an ongoing tuberculous meningitis study from 2014 to 2016 in Lusaka. JCV regulatory region was further characterized by duplex PCR in patients' urine and CSF. Of 440 HIV+ patients, 14 (3%) had detectable JCV DNA in their CSF (age 18-50; CD4+ T cells counts 15-155 × 106/µl) vs 0/60 HIV- patients. The main clinical manifestations included altered mental status and impaired consciousness consistent with advanced PML. While prototype JCV was identified by duplex PCR assay in the CSF samples of all 14 PML patients, only archetype JCV was detected in their urine. All PML Zambian patients tested were seropositive for JCV compared to 46% in a control group of HIV+ and HIV- Zambian patients without PML. PML occurs among HIV-infected individuals in Zambia and is caused by CNS infection with prototype JCV, while archetype JCV strains are present in their urine. JCV seroprevalence is comparable in Zambia and the USA, and PML should be included in the differential diagnosis of immunosuppressed individuals presenting with neurological dysfunction in Zambia.

Nano-based approach to combat emerging viral (NIPAH virus) infection.

Emergence of new virus and their heterogeneity are growing at an alarming rate. Sudden outburst of Nipah virus (NiV) has raised serious question about their instant management using conventional medication and diagnostic measures. A coherent strategy with versatility and comprehensive perspective to confront the rising distress could perhaps be effectuated by implementation of nanotechnology. But in concurrent to resourceful and precise execution of nano-based medication, there is an ultimate need of concrete understanding of the NIV pathogenesis. Moreover, to amplify the effectiveness of nano-based approach in a conquest against NiV, a list of developed nanosystem with antiviral activity is also a prerequisite. Therefore the present review provides a meticulous cognizance of cellular and molecular pathogenesis of NiV. Conventional as well several nano-based diagnosis experimentations against viruses have been discussed. Lastly, potential efficacy of different forms of nano-based systems as convenient means to shield mankind against NiV has also been introduced.

Favipiravir (T-705) protects against Nipah virus infection in the hamster model.

Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Favipiravir has demonstrated efficacy against a broad spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae families, and the Bunyavirales order. We now demonstrate that favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice daily oral or once daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virus. This first successful treatment of henipavirus infection in vivo with a small molecule drug suggests that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections.

Nipah and Hendra virus infectious diseases.

Nipah and Hendra virus were first identified in mid 1990s in Australia and Malaysia, caus- ing epidemics with high mortality rate in affected animals and humans. Since their first emer- gence, they continued to re-emerge in Australia and South East Asia almost every year. Nipah and Hendra virus were classified in the new genus Henipavirus because of their un- common features amongst Paramyxoviridae. Henipaviruses are zoonotic paramyxoviruses with a broad tropism, and cause severe acute respiratory disease and encephalitis. Their high virulence and wide host range make them to be given Biosecurity Level 4 status. This review summarizes details of Henipavirus emergence, reservoir hosts and pathology, and introduce recent progress in vaccines and antivirals.

Mission critical: mobilization of essential animal models for Ebola, Nipah, and Machupo virus infections.

The reports for Ebola virus Zaire (EBOV), Nipah virus, and Machupo virus (MACV) pathogenesis, in this issue of Veterinary Pathology, are timely considering recent events, both nationally and internationally. EBOV, Nipah virus, and MACV cause highly lethal infections for which no Food and Drug Administration (FDA) licensed vaccines or therapies exist. Not only are there concerns that these agents could be used by those with malicious intent, but shifts in ecological distribution of viral reservoirs due to climate change or globalization could lead to more frequent infections within remote regions than previously seen as well as outbreaks in more populous areas. The current EBOV epidemic shows no sign of abating across 3 West African nations (as of October 2014), including densely populated areas, far outpacing infection rates of previous outbreaks. A limited number of cases have also arisen in the United States and Europe. With few treatment options for these deadly viruses, development of animal models reflective of human disease is paramount to combat these diseases. As an example of this potential, a new treatment compound, ZMapp, that had demonstrated efficacy against EBOV infection in nonhuman primates (NHPs) received an emergency compassionate use exception from the FDA for the treatment of 2 American medical workers infected with EBOV, and they are currently virus free and recovering.

Recent developments in experimental animal models of Henipavirus infection.

Hendra (HeV) and Nipah (NiV) viruses (genus Henipavirus (HNV; family Paramyxoviridae) are emerging zoonotic agents that can cause severe respiratory distress and acute encephalitis in humans. Given the lack of effective therapeutics and vaccines for human use, these viruses are considered as public health concerns. Several experimental animal models of HNV infection have been developed in recent years. Here, we review the current status of four of the most promising experimental animal models (mice, hamsters, ferrets, and African green monkeys) and their suitability for modeling the clinical disease, transmission, pathogenesis, prevention, and treatment for HNV infection in humans.

A treatment for and vaccine against the deadly Hendra and Nipah viruses.

Hendra virus and Nipah virus are bat-borne paramyxoviruses that are the prototypic members of the genus Henipavirus. The henipaviruses emerged in the 1990s, spilling over from their natural bat hosts and causing serious disease outbreaks in humans and livestock. Hendra virus emerged in Australia and since 1994 there have been 7 human infections with 4 case fatalities. Nipah virus first appeared in Malaysia and subsequent outbreaks have occurred in Bangladesh and India. In total, there have been an estimated 582 human cases of Nipah virus and of these, 54% were fatal. Their broad species tropism and ability to cause fatal respiratory and/or neurologic disease in humans and animals make them important transboundary biological threats. Recent experimental findings in animals have demonstrated that a human monoclonal antibody targeting the viral G glycoprotein is an effective post-exposure treatment against Hendra and Nipah virus infection. In addition, a subunit vaccine based on the G glycoprotein of Hendra virus affords protection against Hendra and Nipah virus challenge. The vaccine has been developed for use in horses in Australia and is the first vaccine against a Biosafety Level-4 (BSL-4) agent to be licensed and commercially deployed. Together, these advances offer viable approaches to address Hendra and Nipah virus infection of livestock and people.

Hendra virus: an emerging paramyxovirus in Australia.

Hendra virus, first identified in 1994 in Queensland, is an emerging zoonotic pathogen gaining importance in Australia because a growing number of infections are reported in horses and people. The virus, a member of the family Paramyxoviridae (genus Henipavirus), is transmitted to horses by pteropid bats (fruit bats or flying foxes), with human infection a result of direct contact with infected horses. Case-fatality rate is high in both horses and people, and so far, more than 60 horses and four people have died from Hendra virus infection in Australia. Human infection is characterised by an acute encephalitic syndrome or relapsing encephalitis, for which no effective treatment is currently available. Recent identification of Hendra virus infection in a domestic animal outside the laboratory setting, and the large range of pteropid bats in Australia, underpins the potential of this virus to cause greater morbidity and mortality in both rural and urban populations and its importance to both veterinary and human health. Attempts at treatment with ribavirin and chloroquine have been unsuccessful. Education, hygiene, and infection control measures have hitherto been the mainstay of prevention, while access to monoclonal antibody treatment and development of an animal vaccine offer further opportunities for disease prevention and control.