Nipah Virus (NiV)- An Overview

Nipah virus (NiV) is a type of RNA virus that belongs to the family Paramyxoviridae and the genus Henipavirus. It is a zoonotic virus, meaning that it can spread between animals and humans. The natural reservoir of NiV is fruit bats of the Pteropodidae family, also known as flying foxes. NiV can also infect pigs and other domestic animals, as well as cause severe disease and death in humans.

The Nipah virus (NiV) is an enveloped virus belonging to the family Paramyxoviridae. It consists of a negative-sense, single-stranded, and non-segmented RNA genome with helical nucleocapsid. The nucleocapsid, phosphoprotein, and long polymerase constitute the viral ribonucleoprotein. The nucleocapsid is surrounded by the matrix protein embedded with fusion proteins and glycoproteins that protrude as spikes, responsible for cellular attachment and host cell entry. On average, the NiV are larger than the typical paramyxoviruses with sizes ranging from 40 to 1900nm. The virus also differs from other paramyxoviruses in having the reticular cytoplasmic inclusions close to the endoplasmic reticulum. The virus has a close similarity to the Hendra virus (HeV) with only minor ultrastructural differences and also shows significant cross-reactivity on various serological tests. The two strains; Malaysian (MY) and Bangladesh (BD) strains have approximately 92% sequence similarity but show differences in their pathogenicity and transmission.

Nipah virus (NiV) is a zoonotic virus that can infect a wide range of animals and humans. It was first recognized in 1999 during an outbreak among pig farmers in Malaysia and Singapore. Since then, it has caused sporadic outbreaks in Bangladesh, India, and the Philippines. The case fatality rate of NiV infection in humans is estimated at 40% to 75%, depending on the outbreak and the local health system.

NiV can be transmitted to humans from:

• Direct contact with infected animals, such as bats or pigs, or their body fluids (such as blood, urine or saliva)
• Consumption of food products that have been contaminated by body fluids of infected animals (such as palm sap or fruit contaminated by an infected bat)
• Close contact with a person infected with NiV or their body fluids (including nasal or respiratory droplets, urine, or blood)

The natural reservoir of NiV is the fruit bat of the genus Pteropus, also known as flying foxes. These bats can shed the virus in their saliva, urine, and feces, and contaminate fruits, palm sap, or water sources that they visit. Pigs can also become infected with NiV by eating fruits dropped by bats or drinking contaminated water. Pigs can then transmit the virus to other pigs and humans through respiratory secretions and contact with tissues.

Nipah virus (NiV) is a highly pathogenic paramyxovirus that can cause severe respiratory and neurological disease in humans and animals. The virus replicates and spreads through different routes and mechanisms in the host, leading to various clinical manifestations and outcomes.

Replication of NiV

The replication cycle of NiV involves the following steps:

• Attachment/Adsorption: The virus attaches to its host cell through the viral attachment glycoprotein (G) that binds to the cellular receptor ephrin-B2 or ephrin-B3, which are expressed on various tissues such as endothelium, neurons, respiratory epithelium, and placenta. The G protein also mediates the fusion of the viral envelope with the host membrane through the fusion protein (F), which is activated by proteolytic cleavage.
• Penetration and Biosynthesis: The virus enters the cell by endocytosis or direct fusion and releases the viral ribonucleoprotein (RNP) complex into the cytoplasm. The RNP consists of the negative-sense, single-stranded RNA genome encapsidated by the nucleoprotein (N), phosphoprotein (P), and large protein or RNA polymerase (L). The viral RNA serves as a template for the transcription of viral mRNAs by the L protein, which are then translated into viral proteins by the host ribosomes. The P gene also encodes three nonstructural proteins by RNA editing (V, W, and C) that modulate the host immune response. The viral RNA also serves as a template for the replication of new viral genomes by the L protein.
• Assembly: The assembly of new virions occurs at the plasma membrane or in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). The N, P, and L proteins form new RNP complexes that associate with the matrix protein (M), which mediates the budding of virions. The F and G proteins are incorporated into the viral envelope by interacting with the M protein.
• Release: The virions are released from the cell by exocytosis or budding, carrying the F and G proteins on their surface.

Pathogenesis of NiV

The pathogenesis of NiV infection depends on several factors, such as the route of exposure, viral strain, host species, immune status, and genetic susceptibility. The virus can enter the host through different routes, such as inhalation, ingestion, direct contact, or nosocomial transmission. The virus can infect various cell types and tissues, such as respiratory epithelium, endothelium, neurons, lymphoid tissue, kidney, spleen, liver, and placenta. The virus can also cross the blood-brain barrier (BBB) and the placental barrier.

The main targets of NiV infection are the endothelial cells and neurons, which are responsible for causing vascular leakage and encephalitis. The virus induces apoptosis and necrosis of these cells, leading to inflammation, edema, hemorrhage, thrombosis, and hypoxia. The virus also disrupts the tight junctions between endothelial cells and alters their permeability. The virus also triggers the production of pro-inflammatory cytokines and chemokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 alpha (MIP-1α), which recruit and activate immune cells and exacerbate tissue damage.

The virus also evades and suppresses the host immune response by various mechanisms. For example:

• The V and W proteins interfere with the type I interferon (IFN) signaling pathway by binding to STAT1 and STAT2 transcription factors and preventing their nuclear translocation.
• The C protein inhibits the activation of NF-κB transcription factor by blocking its phosphorylation.
• The F protein induces apoptosis of T cells by activating caspase-8.
• The G protein downregulates the expression of ephrin-B2 on immune cells, impairing their migration and function.

The outcome of NiV infection depends on the balance between viral replication and host immune response. In some cases, the infection may be asymptomatic or mild. In other cases, it may cause severe respiratory or neurological disease that can be fatal. Some survivors may develop relapse or late-onset encephalitis or psychiatric disorders.

Nipah virus infection can cause mild to severe manifestations, including encephalitis and ultimately death. The incubation period of the virus generally ranges from 4 to 14 days. However, an extended incubation period of 45 days has also been reported. The general symptoms during the initial phase of the infection include:

• Fever
• Headache
• Cough
• Sore throat
• Difficulty in breathing
• Myalgia (muscle aches)
• Vomiting

Severe symptoms may follow which can progressively lead to coma within 24-48 hours. The symptoms may include:

• Disorientation
• Drowsiness
• Confusion
• Seizures
• Coma
• Brain swelling (encephalitis)

Certain patients show brainstem dysfunction like abnormal doll’s eye reflex, pupillary reflexes, vasomotor changes, seizures, and myoclonic jerks. A characteristic feature of the NiV infection includes relapse or late-onset encephalitis, some of which can occur months or years after the acute infection. Some patients also develop psychiatric manifestations including depression, personality changes, lack of concentration, and loss of verbal and/or visual memory. Differences in clinical manifestations were also observed between the different strains during the outbreaks in Malaysia and India. Respiratory illness like cough, respiratory distress, and atypical pneumonia was observed in 70% of the patients along with a higher mortality rate of 70% in the outbreak in India and Bangladesh as compared to the outbreak in Malaysia where no significant respiratory involvement was observed and had a relatively lower mortality rate of 40%.

The diagnosis of NiV infection can be done during illness or after recovery. Different tests are available to diagnose NiV infection. During early stages of the illness, laboratory testing can be conducted using real-time polymerase chain reaction (RT-PCR) from throat and nasal swabs, cerebrospinal fluid, urine, and blood. Later in the course of illness and after recovery, testing for antibodies is conducted using an enzyme-linked immunosorbent assay (ELISA). Early diagnosis of NiV infection can be challenging due to the non-specific early symptoms of the illness. However, early detection and diagnosis are critical to increase chances of survival among infected individuals, to prevent transmission to other people, and to manage outbreak response efforts. NiV should be considered for people with symptoms consistent with NiV infection who have been in areas where Nipah is more common, such as Bangladesh or India—particularly if they have a known exposure. Other diagnostic methods include immunohistochemistry on formalin-fixed tissues from different sites including brain, lung, spleen, kidney, and lymph nodes; virus isolation on Vero cell line; and serum neutralization test. The specimen for the serological testing should be collected 10-14 days after the onset which may include throat swabs, urine, blood, and/or CSF for diagnosis. The specimen should be processed in a BSL-4 laboratory. However, it can also be processed in a BSL-2 laboratory after virus inactivation through sample irradiation.

Currently, there are no licensed treatments available for Nipah virus (NiV) infection. Treatment is limited to supportive care, including rest, hydration, and treatment of symptoms as they occur. Some of the symptoms that may require treatment include fever, headache, cough, sore throat, difficulty in breathing, myalgia, vomiting, disorientation, drowsiness, confusion, seizures, coma, and brain swelling.

There are, however, immunotherapeutic treatments (monoclonal antibody therapies) that are currently under development and evaluation for the treatment of NiV infections. One such monoclonal antibody, m102.4, has completed phase 1 clinical trials and has been used on a compassionate use basis. In addition, the antiviral treatment remdesivir has been effective in nonhuman primates when given as post-exposure prophylaxis and may be complementary to immunotherapeutic treatments. The drug ribavirin was used to treat a small number of patients in the initial Malaysian NiV outbreak, but its efficacy in people is unclear.

Due to the limited treatments available for the NiV infection, the prevention of the disease must be of high priority. Despite being one of the priority pathogens of the WHO with high fatality rates, there are still no vaccines that are effective and licensed for the NiV infection for human use. However, vaccines against the Nipah virus developed by Public Health Vaccines, the University of Tokyo, and the University of Oxford are in their preclinical trials with plans to test their safety and efficacies in the next few years. Some preventive measures for the disease include:

• Interventions to prevent farm animals from being infected with the virus by preventing them from eating fruits contaminated with the virus through the fruit bats
• Farms should not be near fruit trees that attract the bats
• Consumption of contaminated sap must be avoided
• Installation of physical barriers to prevent the access of the trees by the bats
• The specimens must be handled in proper biosafety cabinets with minimal aerosol formation procedures
• Patients or farm animals suspected of NiV infection must be immediately isolated
• In high-risk areas for the disease, hospitals and health care centers must be prepared for the proper screening and management of possible outbreaks
• Proper handwashing and hygiene practice must be exercised before and after handling specimens or contact with the patient

References:

Chua et al., 2000

Lee et al., 2017

Guillaume et al., 2004

Lo et al., 2012

Escaffre et al., 2013

Mathieu et al., 2015

Sejvar et al., 2007

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