Phylogeography, Transmission, and Viral Proteins of Nipah Virus
Nipah virus (NiV), a zoonotic paramyxovirus belonging to the genus Henipavirus, is classified as a Biosafety Level-4 pathogen based on its high pathogenicity in humans and the lack of available vaccines or therapeutics. Since its initial emergence in 1998 in Malaysia, this virus has become a great threat to domestic animals and humans. Sporadic outbreaks and person-to-person transmission over the past two decades have resulted in hundreds of human fatalities. Epidemiological surveys have shown that NiV is distributed in Asia, Africa, and the South Pacific Ocean, and is transmitted by its natural reservoir, Pteropid bats. Numerous efforts have been made to analyze viral protein function and structure to develop feasible strategies for drug design. Increasing surveillance and preventative measures for the viral infectious disease are urgently needed.
KeywordsNipah virus Viral transmission Geographical distribution Protein structure
In February 2018, Nipah Virus (NiV) infection was listed as a priority disease posing a public health risk by the World Health Organization (http://www.who.int/blueprint/en/). NiV was named after Kampung Sungai Nipah (Nipah River Village) in Malaysia, where it was first isolated in 1998, before its subsequent spread into Singapore via exported pigs in 1999, leading to the abattoir worker infections (CDC 1999a, b; Paton et al. 1999; Epstein et al. 2006). In 2001, human cases of NiV infection were discovered independently in India and Bangladesh, and since then, infections have been observed annually in Bangladesh, and human-to-human transmission through direct contact with infected individuals is common (Hsu et al. 2004; Chadha et al. 2006a, b). In 2007, an NiV outbreak occurred in India, killing five people (Arankalle et al. 2011). In 2018, NiV infection was ongoing in Kerala, India, with 16 cases succumbed (Paul 2018). In 2014, a serious illness most probably caused by NiV was reported in several people after contact with infected horses or patients in the Philippines (Ching et al. 2015). NiV infection can cause fever and encephalitis in humans and a neurological and respiratory syndrome in pigs or horses (Lee et al. 1999; CDC 1999a, b). To date, over 600 human cases of NiV infection have been reported in South Asia and South-East Asia, with fatality ranging from 40% to 70%, accordingly it poses a major threat to human health (Clayton 2017).
NiV has a wide range of hosts, from its natural reservoir Pteropid bats to humans, horses, dogs, cats, cows, and pigs (Calisher et al. 2006; Halpin et al. 2011; Weatherman et al. 2018). Close contact with infected patients (Tan and Tan 2001) or domestic animals (e.g., pigs and horses) plays an important role in the spread of NiV (Clayton 2017). Furthermore, palm sap is also currently regarded as a crucial NiV transmission medium in Bangladesh (Luby et al. 2006; Nahar et al. 2010; Rahman et al. 2012). Intraspecific transmission (in bats, pigs, and horses) is also possible via saliva, urine or secretions upon high density populations of animals (Middleton et al. 2007; Weatherman et al. 2018). In this review, an overview of recent studies on the geographical and phylogenetic properties, transmission, and protein structure and function of NiV is provided.
Geographical Distribution of Nipah Virus
Hosts and Transmission of Nipah Virus
Viral Genomics and Phylogenetics
Based on the time-scaled tree constructed using the currently available viral genomes, the time to the most recent common ancestor (tMRCA) of NiV could be dated to 1356 (95% highest posterior density, 95% HPD: 482—1884). The strains were divided into two lineages (NiV-Bangladesh, n = 4, and NiV-Malaysia, n = 11), with different clinical features and transmission routes in Bangladesh and Malaysia (Fig. 4B). Due to the limited viral genomes available, the detailed divergent time of Bangladesh and Malaysia lineages needs further investigation. More frequent person-to-person contact and more severe respiratory disease have been observed in Bangladesh than in Malaysia (Goh et al. 2000; Chong et al. 2008; Hossain et al. 2008), consistent with the higher level of viral replication in ferrets for NiV-Bangladesh than NiV-Malaysia (Clayton et al. 2012). However, a recent study suggested that social and environmental factors impact the spread of NiV (Clayton and Marsh 2014; Clayton et al. 2016). In Malaysia, no person-to-person transmission was reported when NiV emerged in 1998 and NiV strains derived from humans were isolated in 1999–2000 (Fig. 4B), whereas, in Bangladesh, NiV has appeared nearly annually since 2001 along with significant human-to-human transmission. Thus, comparative genomics and reverse genetics approaches are required to uncover the different features between NiV-Bangladesh and NiV-Malaysia.
Viral Protein Function and Structure
Nipah virus has an approximately 18.2 kb genome encoding six structural proteins and three nonstructural proteins. The viral ribonucleocapsid (RNP) surrounded by the viral envelope consists of its genome and the N protein, which is essential for the viral life cycle as a template for RNA-dependent RNA-polymerase (RdRp), composed of polymerase L and a polymerase cofactor P (Diederich and Maisner 2007; Cox and Plemper 2017). Within the RNP, N is responsible for viral genome wrapping and facilitates viral replication and transcription (Lee et al. 2012). The synthesis of viral mRNA is catalyzed by L and P (Morin et al. 2013), and the latter also inhibits interferon signaling via host STAT-1 (Lo et al. 2012) and acts as a chaperone of N0 (the unassembled form of N) to prevent it nonspecific binding to host RNA (Habchi and Longhi 2012). The M protein contributes to viral assembly and release (Dietzel et al. 2015). G and F are two important surface glycoproteins of NiV; the former induces viral attachment to two cellular receptors, ephrin-B2 and ephrin-B3, despite a lack of hemagglutination or neuraminidase activity (Bonaparte et al. 2005; Negrete et al. 2005, 2006; Bishop et al. 2007). And this subsequently triggers F-mediated membrane fusion between virus and host cells (Bossart et al. 2002; Tamin et al. 2002). The nonstructural protein C participates in the host immune response and serves as a virulence factor (Mathieu et al. 2012).
Knowing the geographic distribution and transmission of a virus is the priority for the control of infection and resolving the structure and function of viral protein is the basis for anti-viral drug development. In this review, we are focusing on these aspects of the NiV. As a huge natural reservoir of viruses, including NiV, bats have been under renewed interest. Bats appear asymptomatic when infected by many viruses and play a pivotal role in viral spillover. Continually emerging and reemerging viruses from bats have been reported. In 2012, a novel rubula-like paramyxovirus from fruit bats was found to be responsible for a series of severe clinical symptoms appearing on a female wildlife biologist who performed a 6-week field exploration in South Sudan and Uganda (Albariño et al. 2014). In 2017, a huge gene pool of SARS-like coronaviruses was found in horseshoe bats in a cave in Yunnan province, China, which indicated the close relationship between those isolates and SARS coronavirus (Hu et al. 2017). Recently, a novel bat-originated coronavirus, swine acute diarrhea syndrome coronavirus (SADS-CoV), which led to more than 24,000 piglet deaths at four pig farms in Guangdong province, China was reported (Zhou et al. 2018). In particular, a similar transmission pathway between SADS-CoV and NiV (bats to pigs) occurs, although no human infection was found. More exposure to areas of bat movement augments extremely risk of infecting bat-derived viral diseases. Unfortunately, human activities are altering the frequency of contact with bats. For instance, deforestation in tropical zones forces bats to migrate from their habitats to human areas (Daszak et al. 2001) and many bats are hunted for consumption or so-called harmfulness (Enchéry and Horvat 2017). Therefore, continuous surveillance, reducing human activities that promote contact with bats, and enhancing scientific research will help the prevention and control of bat-derived viral infectious disease. Given limited viral genomes available, restrictions on investigating the origin and evolution of Nipah virus have been imposed; therefore, continuous epidemiological surveillance must be strengthened in the future. In addition, several structures of viral proteins remain unknown; accordingly, it is necessary to increase basic research efforts on protein structures and functional analyses of viral proteins to provide data for antiviral drug and vaccine development.
This work was supported by National Key Research and Development Program (2016YFC1200800) and Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Animal and Human Rights Statement
This article does not contain any studies with human or animal subjects performed by any of the authors.
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