How Ebola Virus Infects the Host Cells

Ebola virus disease (EVD), formerly known as the Ebola haemorrhagic fever is a virus transmitted to people from wild animals and is transmitted between humans, with the first outbreaks that occurred in remote villages in Central Africa near tropical rainforests (WHO, 2018). Ebola virus disease was epidemic in West Africa in 2014, and when the epidemic was over in March 2016, 11,325 confirmed, probable, and suspected deaths occurred with the total EVD cases numbered 28,652 (Ebola Virus Disease and Ebola Vaccines, 2014). It is rare disease with high fatality rate if left untreated. Its previous name gives us the information on the type of illness it causes, which is the haemorrhagic fever. According to the Centers for Disease Control and Prevention, The Ebola disease is caused by a group of a virus species called Zaire ebolavirus under the genus Ebolavirus (2018). Aside from fever, vertigo, muscle pain, fatigue, vomiting and diarrhoea, Ebola virus disease can manifest the most severe signs and symptoms which are damages to blood vessels, and extensive internal and external bleeding called haemorrhage. (Baylor College of Medicine, n.d). Despite the reoccurrence of Ebola in 2014, no drugs were discovered that could cure Ebola directly. However, Cardile, Warren, Martins, Reisler, and Bavari (2017) stated that, Numerous therapeutics were explored or developed during the outbreak, including repurposed drugs, nucleoside and nucleotide analogues (BCX4430, brincidofovir, favipiravir, and GS-5734), nucleic acidbased drugs (TKM-Ebola and AVI-7537), and immunotherapeutics (convalescent plasma and ZMapp). The process of how the Ebola virus infects the host's cells is by attachment, uncoating and fusion, transcription and replication, assembly and budding.

        The first stage of Ebola infection is the attachment of the Ebola virus to the host's cells. According to Kawaoka (2005), upon entry into the host, Embedded within the host-derived lipid envelope of Ebola virus are glycoprotein spikes that bind to cells and mediate fusion between the viral envelope and the host cell membrane, enabling the virus to release its contents into the host-cell cytoplasm. This simply means that the virus binds to the surface proteins on the host's cell membrane. Then, the interaction between the substances on the virus's membrane and the host's cell's cell membrane occurs, allowing the virus to enter the host's cell. The virus infects several types of immune cells, mainly dendritic cells that are responsible for the body's first line of defense, causing the dysfuntionality of the dendritic cells to activate the T-lymphocytes to fight against the infection of the virus (Servick, 2014). The virus are then able to replicate successfully without any interference from the body's immune system.

The next step is uncoating and fusion of the Ebola virus into the host cell cytoplasm. In order for the virus to reproduce, it must enter the host cell (Haywood, 2010). Based on Yu, et al., (2017), the uncoating step for Ebola virus involved several endocytic pathways and factors such as what type of host cell and the size of the viral particles. Uncoating of the viral particles into the endosomal membranes compromised of the virus fusion to the host cell membrane. The uncoating of the genetic informations, proteins, and other particles of the Ebola virus is determined by the host's own body cells. The Ebola virus received signals from the host's cell to start the uncoating of the virus particles into the cytoplasm. The host enzyme cleaved precursor glycoprotein resulting in glycoprotein-1, glycoprotein-2 and other proteins. Glycoprotein-2 is an important protein for the fusion of the Ebola viral membrane to the host cell. As stated by Howard (2005) in his book, it formed the trimeric alpha-helical, rod shaped structure to function in the fusion membrane process. The receptors of the glycoprotein-1 act upon the fusion loop of glycoprotein-2 to prevent early on fusion process. The fusion loop domain is considered to start the membrane fusion process. The Niemann-Pick C1 (NPC1) is also an important component of this process. The NPC1 acts as a guidance to the Ebola virus membrane to locate where the fusion is to be taken place. The mechanism of NPC1 in the Ebola virus infection to the host cell is yet to be further research upon.

The third step is transcription and replication of the Ebola virus once it entered the host cytoplasm. Ebola virus is categorized under the family Filoviridae. For that type of virus family, the transcription and replication usually involved the negative single-stranded ribonucleic acid (ssRNA). Like any other negative ssRNA, it contains genome where all the genetic informations are stored, it is encapsulated by nucleoprotein (Yu, et al., 2017). M??hlberger (2007) stated that, the negative ssRNA is transcribed by the RNA-dependent RNA-polymerase to further form the complex structure ribonucleprotein (RNP). RNP acts as a messenger-RNA (mRNA) to trigger the host cell to produce more cellular particles. Without the RNA-dependent RNA-polymerase, viral mRNA will not be able to react (Howard, 2005). The virion set free the RNP upon the entry of viral particles to the host cell membrane and membrane fusion. Furthermore, the RNA is to assist the replication of Ebola virus as a template. The Ebola virus take advantages of the existing cellular structures from the transcription of the ssRNA in the cytoplasm to replicate itself. The transcription and replication is an important step for the virus to infect the host cell due to the virus having its own complement machinery, the components are an excellent mark for antiviral actions. 

The fourth step is assembly. According to Yu et al. (2017), the assembly step starts with the formation of nucleocapsids that later accumulates and transported to the plasma membrane for budding. Throughout this phase, glycoprotein and nucleocapsid protein both play a major role. Firstly, glycoprotein is transported to the plasma membrane after being synthesized in the endoplasmic reticulum. Next, acylation process will take over to produce modified viral glycoprotein and also take place in particle formation, virus assembly and budding (Ito, Watanabe, Takada & Kawaoka, 2001). Then, the modified glycoprotein are transported to late endosomes to meet the viral protein 40 for assembly and budding.

Meanwhile, in the core of nucleocapsid physical interaction between nucleocapsid helices and viral protein through 50 C-terminal amino acids is happening and later took in by viral like particle induced by viral protein 40 (Takamatsu, Kolesnikova & Becker, 2018).Yu et al. (2017) stated that nucleocapsid is proven to assembled into helical tubes, forms a structure called nucleocapsid-like structure with both viral protein 35 and viral protein 24 and soon, micro tubules along with viral protein 40 transported the nucleocapsid-like structure to the surface of cell membrane causing nucleocapsid-viral protein 40 interaction to happen and resulting to incorporation of virions on the cell membrane. Therefore, the assembly phase is important for transportation to plasma membrane and formation of virions.

The last step is budding. There are 2 major processes in budding which are interaction of viral protein 40 and inner leaflet and interaction of glycoprotein 2 and tetherin. Adu-Gyamfi, Digman, Gratton and Stahelin (2012) stated that viral protein 40 consist of 2 domains which are N-terminal domain, the oligomerization domain and C-terminal domain, the hydrophobic loop with flexibility. This shows that viral protein 40 have the components that are associated with phosphatidylserine. When binding of viral protein to phosphatidylserine-containing membrane happen, some rearrangements and regulations take place thus allowing the viral protein 40 to attach to the membrane (Yu et al., 2017). In interaction of glycoprotein 2 and tetherin, theterin act as virion retention inducer while glycoprotein served as tetherin antagonism (Lopez et al., 2010). The budding of Ebola virus can be detected on three places which are plasma membrane of cell, intracellular membrane of multivesicular body and late endosome where glycoprotein and viral protein 40 met. However, the mechanism on how viral protein 40 achieve the final step in its lifecycle still remain unclear and need future research (Licata, Johnson, Han & Harty, 2004).

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