Le Infezioni in Medicina, n. 2, 117-127, 2019 REVIEW 117 Nipah virus The rising epidemic: a review Rohan Kumar Ochani, Simran Batra, Asim Shaikh, Ameema Asad MBBS, Department of Internal Medicine, Dow University of Health Sciences, Karachi, Pakistan SUMMARY The Nipah virus was discovered twenty years ago, and sub-continent, Indonesia, Southeast Asia, Pakistan, there is considerable information available regarding southern China, northern Australia and the Philippines, the specificities surrounding this virus such as trans- as demonstrated by the multiple outbreaks in 2001, mission, pathogenesis and genome. Belonging to the 2004, 2007, 2012 in Bangladesh, India and Pakistan as Henipavirus genus, this virus can cause fever, enceph- well as the initial outbreaks in Malaysia and Singapore. alitis and respiratory disorders. The first cases were re- Multiple routes of the viremic spread in the human ported in Malaysia and Singapore in 1998, when affect- body have been identified such as the central nervous ed individuals presented with severe febrile encepha- system (CNS) and respiratory system, while virus lev- litis. Since then, much has been identified about this els in the body remain low, detection in the cerebro- virus. These single-stranded RNA viruses gain entry spinal fluid is comparatively high. The virus follows into target cells via a process known as macropinocyto- an incubation period of 4 days to 2 weeks which is fol- sis. The viral genome is released into the cell cytoplasm lowed by the development of symptoms. The primary via a cascade of processes that involves conformational clinical signs include fever, headache, vomiting and changes in G and F proteins which allow for attach- dizziness, while the characteristic symptoms consist ment of the viral membrane to the cell membrane. In of segmental myoclonus, tachycardia, areflexia, hypo- addition to this, the natural reservoirs of this virus tonia, abnormal pupillary reflexes and hypertension. have been identified to be fruit bats from the genus The serum neutralization test (SNT) is the gold stand- Pteropus. Five of the 14 species of bats in Malaysia have ard of diagnosis followed by ELISA if SNT cannot be been identified as carriers, and this virus affects horses, carried out. On the other hand, treatment is supportive cats, dogs, pigs and humans. Various mechanisms of since there a lack of effective pharmacological thera- transmission have been proposed such as contamina- py and only one equine vaccine is currently licensed tion of date palm saps by bat feces and saliva, noso- for use. Prevention of outbreaks seems to be a more comial and human-to-human transmissions. Physical viable approach until specific therapeutic strategies are contact was identified as the strongest risk factor for devised. developing an infection in the 2004 Faridpur outbreak. Geographically, the virus seems to favor the Indian Keywords: Nipah virus, outbreaks, vaccine. n INTRODUCTION nucleotides long, which accounts for them to be 15% longer than others in their family. Moreo- iscovered two decades ago as aetiolog- ver, the genetic characteristics found in the genus Dic agent of a zoonotic disease, Nipah virus Henipavirus, include the unique, 3’ leader and 5’ (NiV), is a member of genus Henipavirus in the trailer sequences, which promote transcription Paramyxoviridae family. Unlike the Hendra Vi- and replication of genomic RNA, respectively [1]. rus, which is 18234 nucleotides long, NiV is 18246 Categorized as Category C priority pathogen by the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Corresponding author Infectious Diseases (NIAID), its clinical manifes- Rohan Kumar Ochani tations include fever, encephalitis, and in severe E-mail: [email protected] conditions, respiratory and pulmonary disorders 118 R.K. Ochani, S. Batra, A. Shaikh, A. Asad affecting numerous systems of the body [2]. Af- The virus particles are pleomorphic in shape, al- ter its discovery from Sungai Nipah (Nipah River tering from spherical to filamentous, and have a Village), where its name originally came from, the diameter of approximately between 40 and 600 first cases characterized by severe febrile enceph- nm [6]. NiV is covered with a lipid capsule encom- alitis in humans were reported in Singapore and passing a nucleocapsid. A single layer of surface Malaysia, between 1998 and 1999 [3]. projections surrounds NiV envelope, showing the Transmission of NiV has been reported by vari- attachment and fusion proteins. The nucleocapsid ous ways which include human-to-human trans- core comprises of the genomic RNA, nucleocapsid mission and food-borne transmission [2]. The protein, polymerase, and phosphoprotein, while natural reservoir of the virus are bats of genus the envelope comprises of the matrix protein Pteropus; therefore, proximity with bats is one of which preserves the virion structure. Although the reasons for the occurrence of NiV and swal- members of the paramyxovirus family typically lowing of raw date palm sap is another [1]. Fur- have a genomic length of 15,500 nt, the HeV has a thermore, the virus spread in Singapore due to length of 18,234 nt. [7]. handling and holocaust of pigs [4, 5]. The mortal- Entry of the NiV in the target cells is typically ity rate was approximately 40% in Malaysia and through a process of macropinocytosis via the Singapore, compared to 70% in India and Bang- glycoprotein and fusion protein. The two cellular ladesh, where the outbreaks of NiV are frequent. receptors bound in the process are ephrin-b2 and Considering its degree of endemic in South Asia, ephrin-b3, which leads to a conformational change systemic surveillance is required to overcome its of the G and F proteins. Following the receptor recurrence and rising mortality rates [2, 3]. binding F fusion activity is assisted by the glyco- protein via an unknown mechanism, resulting in a conformational change leading to the entry of fu- n METHODS sion peptide into the host cell. Afterwards, the viral Systematic literature review membrane attaches to the cellular plasma mem- For this review, a literature search was conduct- brane leading to the delivery of the core and the ed using PubMed and Google Scholar from their release of the viral genome to the cytoplasm, but inception to November 2018. The search string in- before the entry, the M protein shell and N protein cluded the following keywords: (“Nipah virus”) need to be disrupted due to an unknown mecha- AND (“outbreak” OR “transmission” OR “clinical nism. Moreover, the pathway to transcription and manifestation” OR “neurologic manifestation” OR replication of the Nipah virus is presumed to be “geographic distribution” OR “global distribution” similar to those of other paramyxoviruses. The ba- OR “genomic distribution” OR “etiology” OR “cau- sic functional component needed for the replica- sality” OR “genomic structure” OR “pathogenesis” tion and transcription is the combination of tightly OR “treatment” OR “prevention” OR “control” OR bound negative sense RNA with N proteins and “biosafety” OR “economic burden”). Articles in oth- RNA polymerase complex. The primary transcrip- er than the English language were excluded. tion consists of the RNA polymerase complex to be packaged inside the virion, which copies the viri- NiV genome, structure and replication on RNA (vRNA) and then generates, capped, short Like all other paramyxoviruses, NiV and HeV are uncapped RNAs and polyadenylated mRNAs, en- also single-stranded RNA viruses which replicate coding viral proteins [8, 9]. in the cytoplasm; however, NiV is 12 nucleotides longer than HeV and therefore have the largest Vectors, transmission and reservoirs genome in their family. Right after its emergence The first cases of Nipah virus were recognized in in 1999, Harcourt et al. described the genomic re- pigs showing symptoms of respiratory disease lationship between other paramyxoviruses and and in a few cases, neurological deficits, in 1998 in NiV. The authors also studied to identify the vari- Malaysia. Most pigs had asymptomatic infections ous genes involved in the genomic making of the and a majority of them fully recovered. Exposure virus, which included the nucleocapsid (N), phos- to ill pigs resulted in transmission to humans phoprotein (P), matrix (M), fusion (F), and glyco- where 276 individuals developed encephalitis. protein (G) genes [6]. Unlike other Paramyxoviruses, the Nipah virus Nipah virus - the rising epidemic: a review 119 demonstrates a wide host range, infecting mul- pigs being euthanized, leading to a steep decline tiple species of animals such as horses, cats, and in international trade of the region. However, the dogs, as well as humans. The natural reservoirs for infection did not remain cornered in Malaysia, and the virus are fruit bats from the genus Pteropus. 5 the diseased transmission accelerated when the of 14 bat species in Malaysia have been identified virus afflicted pigs moved 160 miles in the state of as carriers of the virus with Pteropus hypomelanus Negri Sembilan. These pigs from Negri Sembilan and Pteropus vampyrus having the highest rates were kept and slaughtered in an abattoir in Singa- of seroprevalence with the infectious virus being pore, and the virus subsequently spread to the ab- identified in their urine and saliva.Pteropus hypo- attoir workers. An alarming mortality rate of 40% melanus and Pteropus lylei were isolated as being was noted and the majority of patients presented carriers in South and South East Asia.