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We conducted an in-depth characterization of the Nipah virus (NiV) isolate previously obtained from a Pteropus lylei bat in Cambodia in 2003 (CSUR381). We performed full-genome sequencing and phylogenetic analyses and confirmed CSUR381 is part of the NiV-Malaysia genotype. In vitro studies revealed similar cell permissiveness and replication of CSUR381 (compared with 2 other NiV isolates) in both bat and human cell lines. Sequence alignments indicated conservation of the ephrin-B2 and ephrin-B3 receptor binding sites, the glycosylation site on the G attachment protein, as well as the editing site in phosphoprotein, suggesting production of nonstructural proteins V and W, known to counteract the host innate immunity. In the hamster animal model, CSUR381 induced lethal infections. Altogether, these data suggest that the Cambodia bat-derived NiV isolate has high pathogenic potential and, thus, provide insight for further studies and better risk assessment for future NiV outbreaks in Southeast Asia.

Nipah Virus (NiV) is a highly fatal emerging zoonotic virus and a potential threat to global health security. Here we describe the characteristics of the NiV outbreak that occurred in Kerala, India, during May-June 2018. We used real-time reverse transcription polymerase chain reaction analysis of throat swab, blood, urine, and cerebrospinal fluid specimens to detect NiV. Further, the viral genome was sequenced and subjected to phylogenetic analysis. We conducted an epidemiologic investigation to describe the outbreak and elucidate the dynamics of NiV transmission. During 2-29 May 2018, 23 cases were identified, including the index case; 18 were laboratory confirmed. The lineage of the NiV responsible for this outbreak was closer to the Bangladesh lineage. The median age of cases was 45 years; the sex of 15 (65%) was male. The median incubation period was 9.5 days (range, 6-14 days). Of the 23 cases, 20 (87%) had respiratory symptoms. The case-fatality rate was 91%; 2 cases survived. Risk factors for infection included close proximity (ie, touching, feeding, or nursing a NiV-infected person), enabling exposure to droplet infection. The public health response included isolation of cases, contact tracing, and enforcement of hospital infection control practices. This is the first recorded NiV outbreak in South India. Early laboratory confirmation and an immediate public health response contained the outbreak.

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.

The highly infectious Nipah virus (NiV) is classified under the Paramyxoviridae family and is categorized under the genus Henipavirus. NiV spreads to humans through zoonotic transmission from reservoir host bats and other intermediate hosts. It is highly contagious and has a high case fatality rate (CFR) of ~ 40–80%. Only sporadic outbreaks have been reported so far, but like SARS-CoV2, NiV has a high pandemic potential and has been put on the World Health Organization (WHO) priority pathogen list. Currently, no clinically approved antivirals, immunotherapy, or vaccines are available to tackle NiV infection, thereby necessitating further research into its life cycle, transmission, and pathogenesis. This detailed review outlines the origin and spread of the Nipah virus, its modes of transmission, risk factors, its genome, key proteins, pathogenesis, and clinical features. We also discuss different diagnostic approaches and ongoing research to develop therapies ranging from antibodies to vaccines. Key points •Pandemic preparedness for emerging and re-emerging viruses. •Novel approaches for diagnostics and therapeutics for Nipah viruse. •Global threat from biosafety level 4 pathogens. •Animal models for Nipah virus research.

Nipah virus (NiV), a highly lethal zoonotic paramyxovirus, displays strain-specific pathogenicity, yet the molecular basis for this divergence remains elusive. Here, we identify N6-methyladenosine (m6A) modification as a pivotal regulator of NiV replication. Higher m6A methylation levels on viral genomic RNA and mRNAs are associated with the increased virulence observed in the NiV-Malaysia (NiV-M) strain compared to NiV-Bangladesh (NiV-B). Underlying this phenomenon, NiV infection orchestrates a reprogramming of the host m6A machinery by downregulating the methyltransferase METTL3 and the demethylase ALKBH5, while concurrently upregulating m6A reader proteins YTHDF1-3. Both METTL3 and ALKBH5 bind directly to NiV RNA, with METTL3 installing m6A to promote viral replication and ALKBH5 removing them to inhibit it. Strikingly, pharmacological inhibition of m6A modification markedly attenuates NiV replication in vitro and in vivo, underscoring the therapeutic potential of targeting the m6A pathway. Our study establishes m6A as a key determinant of NiV pathogenicity and provides a paradigm for host-directed antiviral strategies against high-risk RNA viruses.

Nipah virus (NiV), a highly pathogenic zoonotic paramyxovirus, causes severe respiratory and neurological disease in humans, with a case-fatality rate around 60%. Descriptions of cases in the clinical setting suggest that the two primary lineages of NiV cause disease with different presentations and outcomes. To define strain-specific differences in disease progression and host responses, African green monkeys were exposed to either the Malaysia (NiV-M) or Bangladesh (NiV-B) strain using a large-particle aerosol exposure. NiV-M infection resulted in a fatality rate of 27%, while NiV-B infection led to a 75% fatality rate characterized by rapid respiratory decline and systemic viral dissemination. Among survivors, NiV-M–infected animals mounted robust immunoglobulin M, immunoglobulin G, and neutralizing antibody responses, whereas NiV-B survivors exhibited weaker and delayed humoral responses. Non-survivors of both strains showed elevated pro-inflammatory cytokines, thrombocytopenia, and multi-organ dysfunction. Imaging showed that NiV-M infection was associated with neuroinflammation and systemic vasculitis, while NiV-B infection caused progressive pulmonary pathology. Histopathological analysis confirmed widespread vasculitis and encephalitis in animals with NiV-M infection and diffuse pulmonary hemorrhage and fibrin thrombi, consistent with vascular injury and coagulopathy, in animals with NiV-B infection. Cytokine profiling and flow cytometry showed a more intense and dysregulated immune response to NiV-B infection. Fatal outcomes in both groups were associated with thrombocytopenia, elevated pro-inflammatory cytokines, and multi-organ dysfunction. This study highlights fundamental differences in virulence, immune evasion, and pathogenesis between NiV strains and underscores the value of the African green monkey aerosol model for evaluating medical countermeasures under conditions that closely mimic natural human exposure.

Nipah virus, a zoonotic pathogen, can cause debilitating disease and death in humans. Currently, countermeasures are limited, with several in various stages of testing but none yet FDA-approved for human use. Evaluation of countermeasure candidates requires safety testing in humans, as well as efficacy testing against lethal challenge in animal models. Herein, we describe the characterization and comparison of the intraperitoneal and intranasal Syrian golden hamster models for Nipah virus strains Malaysia and Bangladesh. Overall, the intraperitoneal route of exposure resulted in a more consistent lethal outcome, regardless of virus strain. Therefore, the IP model was subsequently used to evaluate the use of Favipiravir as a potential positive control for future studies investigating NiV countermeasures. In contrast to prior reported results regarding Favipiravir in Nipah virus-infected hamsters, Favipiravir was only fifty percent effective at preventing death following lethal challenge, regardless of Nipah virus strain. The data suggest that Favipiravir is only partially protective against Nipah virus in hamsters, and, thus, would likely not be an ideal candidate as a positive control in future efficacy studies.

Emerging infectious diseases (EIDs) pose a significant threat to human health, economic stability, and biodiversity. Despite this, the mechanisms underlying disease emergence are still not fully understood, and control measures rely heavily on mitigating the impact of EIDs after they have emerged. Here, we highlight the emergence of a zoonotic Henipavirus , Nipah virus, to demonstrate the interdisciplinary and macroecological approaches necessary to understand EID emergence. Previous work suggests that Nipah virus emerged due to the interaction of the wildlife reservoir (Pteropus spp. fruit bats) with intensively managed livestock. The emergence of this and other henipaviruses involves interactions among a suite of anthropogenic environmental changes, socioeconomic factors, and changes in demography that overlay and interact with the distribution of these pathogens in their wildlife reservoirs. Here, we demonstrate how ecological niche modeling may be used to investigate the potential role of a changing climate on the future risk for Henipavirus emergence. We show that the distribution of Henipavirus reservoirs, and therefore henipaviruses, will likely change under climate change scenarios, a fundamental precondition for disease emergence in humans. We assess the variation among climate models to estimate where Henipavirus host distribution is most likely to expand, contract, or remain stable, presenting new risks for human health. We conclude that there is substantial potential to use this modeling framework to explore the distribution of wildlife hosts under a changing climate. These approaches may directly inform current and future management and surveillance strategies aiming to improve pathogen detection and, ultimately, reduce emergence risk.

The Nipah virus (NiV) is a highly virulent zoonotic infectious agent that poses a significant threat to public health. The virus is characterized by its pleomorphic structure and a single-stranded negative-sense RNA genome. It encodes six structural proteins and three nonstructural proteins. Attachment glycoproteins play a crucial role in allowing the virus to attach to the host cell surface. The matrix protein facilitates the encapsidation of the viral genome and proteins, enabling the formation of mature viral particles. The virus can spread via different routes, including zoonotic spillover and human-to-human transmission. Clinical manifestations include mild respiratory illness and severe and fatal encephalitis. The case fatality rate of Nipah virus infection varies widely, ranging from 40 to 75%, and is regulated by factors such as healthcare availability and quality, the patient's condition, and the virulence of the infecting strain. NiV has been reported in Malaysia, Bangladesh, and India, with fruit bats serving as natural reservoirs. Early detection and prompt response are crucial for controlling outbreaks; however, these efforts are hindered by diagnostic challenges and delayed recognition. The World Health Organization has categorized NiV as a priority pathogen owing to its epidemic potential, recurrent outbreaks, and alarming mortality rates. The persistent transmission dynamics and genetic stability of the Nipah virus among fruit bats require immediate attention and coordinated global action. The present study reviews the epidemiology, clinical features, and modes of transmission of Nipah virus infection, its geographical distribution, and endemic regions, highlighting the challenges in managing disease outbreaks.

Nipah virus receptor Nipah virus, first recognized in 1999, is an emerging disease that causes fatal encephalitis in humans. Its natural host is thought to be the fruit bat but it is also found in pigs and other animals. It could pose a serious threat to the pig-farming industry and there is recent evidence of human-to-human transmission. A crucial receptor that the virus relies on to infect human cells has now been identified, suggesting ways that the infection might be countered by vaccines or drugs. The virus's attachment protein binds to the ephrinB2 receptor. This receptor is critical for normal vascular developmental processes and is present in tissues targeted by Nipah virus. The enzyme EphB4 can block the entry of the virus into the cell. Nipah virus (NiV) is an emergent paramyxovirus that causes fatal encephalitis in up to 70 per cent of infected patients 1 , and there is evidence of human–to–human transmission 2 . Endothelial syncytia, comprised of multinucleated giant-endothelial cells, are frequently found in NiV infections, and are mediated by the fusion (F) and attachment (G) envelope glycoproteins. Identification of the receptor for this virus will shed light on the pathobiology of NiV infection, and spur the rational development of effective therapeutics. Here we report that ephrinB2, the membrane-bound ligand for the EphB class of receptor tyrosine kinases (RTKs) 3 , specifically binds to the attachment (G) glycoprotein of NiV. Soluble Fc-fusion proteins of ephrinB2, but not ephrinB1, effectively block NiV fusion and entry into permissive cell types. Moreover, transfection of ephrinB2 into non-permissive cells renders them permissive for NiV fusion and entry. EphrinB2 is expressed on endothelial cells and neurons 3 , 4 , which is consistent with the known cellular tropism for NiV 5 . Significantly, we find that NiV-envelope-mediated infection of microvascular endothelial cells and primary cortical rat neurons is inhibited by soluble ephrinB2, but not by the related ephrinB1 protein. Cumulatively, our data show that ephrinB2 is a functional receptor for NiV.