Disruption in Momentum, Pandemic An Analysis of the Virology of the SARS-CoV2 Virus

Analysis, Pages 10 (2345 words)

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Introduction

This report will focus on the virological basis of the SARS-CoV-2 virus, more known as COVID-19. The molecular virology basis of the virus, the basis of its infectious cycle, and the mechanism of replication and finally the genomic expansion will be reflected upon. This report is under the supervision of both Dr Clare McVeigh and Dr Ali Charri.

The flu pandemic is one of many. The widespread caused by the Influenza A virus, also labelled as the “Spanish Flu” had lasted from 1918-1919, exploding at the final stages of the first world war, where approximately 50 million individuals had lost their lives due to the virus, that had infected one third of the world’s population (≈500 million people), it was a truly devastating epidemic.

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(Taubenberger & Morens, 2006)

The spanish flu or the ‘La Grippe’ had been caused by an H1N1/A virus of avian ancestry. (CDC, 2019). A study done in 1997 had aimed to evaluate the genetic characteristics of the spanish flu and had successfully sequenced its genomic RNA using autopsial remnants of the virus (formalin-fixed paraffin-embedded tissue), yet there was no certain identification of the reason behind it’s extreme virulency.

However, it was denoted that the 1918 influenza virus is most likely a common ancestor to novel influenza viruses that mutate, reassort and diversify, still circulating annually within human populations, such as the H2N2 & the H3N2 viruses. (Taubenberger, 1997) As a result the 1918 Influenza A virus has been denoted to be “the mother of all pandemics”. (Taubenberger & Morens, 2006)

To put it more precisely, the influenza viruses of the Orthomyxoviridae genus are known to have 4 types denoted as influenza A, influenza B, influenza C and influenza D (Bouvier & Palese, 2008), classified based on the genetic diversification due to reassortment of viral genome with other types of viruses.

Influenza A and B viruses are the types of viruses still spreading within the human population as seasonal epidemics.

Furthermore, influenza A viruses are divided into subsets according to the which of the 18 subtypes of hemagglutinin (H) and the 11 neuraminidase (N) glycoproteins located on the viral surface.These are then further subdivided into clades and subclades. (CDC, 2019)

These findings help us establish that the recurring swarms of viruses are caused by multiple factors such as the infectious nature of the virus, how pathogenic it is, and how it can cause radical consequences to societies.

Gaze at the Present: SARS-CoV 2 of 2019

Overview

The uprising virus is not of unfamiliar origins. COVID-19, also denoted SARS-CoV 2 is a coronavirus belonging to the subfamily Coronavirinae under the Coronaviridae family (deGrootetal., 2012a; Masters and Perlman, 2013). These are positive RNA viruses with a large genome that can range from 27-30 Kb (Liu, 2014)

A brief explanation of the Coronaviridae family: these are a collection of virus strains that can be found populating in different mammalian species, including humans. Four genera were given to the viral family: alphacoronavirus, betacoronavirus, gammacoronavirus and the deltacornonavirus. What differentiates each genre is their species of target, at which gamma and delta coronaviruses infect avian species while the alpha and beta generas infect mammalian populations. (Cormanetal., 2018) Moreover, the gamma and delta coronaviruses share a bird as a common ancestor while the alpha and beta have a bat as theirs. (Li, 2016)

The MERS, SARS CoV and the novel SARS CoV 2 have been characterized to cause severe diseases of the respiratory systems and are due to zoonotic transfer that will be discussed further later on, while the HKU1, NL63, OC43 and 229E are related with mild symptoms and are regular causes of the common cold. (Andersen etal., 2020)

SARS-CoV

Severe Acute Respiratory Syndrome virus surfaced in 2003, identified to have been transmitted to human populations by carnivorous felines such as the wild civet cat. (Cormanetal., 2018) It had caused a global health threat due to its severe effects on the respiratory system.

Studies still find the way the SARS interacts with the immune system of the host to be quite perplexing. A basic “framework” had been illustrated for its interaction, similar to MERS in which the virus affects immune responses that stimulate type 1 interferons (IFN-⍺ and IFN-𝛽) mechanism of action by lowering the production of antiviral cytokines and stimulating the release and synthesis of pro-inflammatory and anti-inflammatory cytokines such as IL-6.Other effects on the immune system include the “induction of neutralizing antibodies by the accessory protein 3a, down regulation of ACE2 expression, triggering of ACE 2 signaling and the stimulation of fibrosis-associated chemokines.” (Liu, 2014) Additional viral proteins produce significant effects induce grave damage such as cell apoptosis induced by proteins E, M and other viral accessory proteins.

MERS

Middle Eastern Respiratory Syndrome had emerged in 2012 and had been denoted to be exclusively transmittable by human-human interactions (Doremalen, 2013). MERS was found to be caused by a zoonotic transfer from dromedary camels (Chuetal., 2014 ). Those infected with MERS had a variety of clinical manifestations such as

The pathogenesis of MERS infection has a similar mechanism of action of the SARS-CoV at which the infection of the epithelial linings of the respiratory tract induces a delayed response of the innate immune system at which IFN production is detained momentarily but is then followed by a significant production of proinflammatory cytokines (IL-1β, IL-6, and IL-8). One significant finding that differentiates this mechanism from SARS-CoV is that MERS replication can occur in both naive and mature monocytes (macrophages), dendritic cells and only T cells when activated. While in contrast SARS fails to do so. (Cormanet.al, 2018)

SARS-CoV 2

This part of the essay entails the specificities of the contemporary SARS-CoV 2 virus. This novel virus had been identified after the eruption of multiple cases initially that were rooted back to a seafood marketplace in Wuhan. Recent research had discovered that the viral strain could have been possibly imported from other locations. Moreover, it has been evident that 2 other viral strains of SARS-CoV2 had been identified even prior to ‘COVID-19’ (Zhouetal., 2020) .No animal had been associated as an intermediate host for this particular virus, however it was assessed that genetic sequences extracted from pangolins had shown a 99% similarity to the genetic sequences of the SARS-CoV 2 virus, making it a highly suspected candidate.(Prompetchara, 2020)

As mentioned previously, the SARS-CoV 2 virus is a positive sense RNA Virus, a positive sense RNA virus asserts that the viral genome of the virus can be readily recognized by the ribosomes of the host cells. This genome consists of a nucleocapsid genome coated by the nucleocapsid protein in means of protection. This genome is also encapsulated by a lipid envelope that is derived from the host lipids. (Li, 2016)

The lipid encasing is speckled with viral proteins. The most prominents of these proteins is the spike protein that has an important role in the entry mechanism of the virus. Another protein to note is the matrix protein denoted as M shown in figure (1). It is a membrane glycoprotein that connects the viral lipid membrane to the nucleocapsid, which is vital for the morphogenesis stage of the viral infectious cycle.

What has changed?

Despite the common ancestry of these three viruses, they still exhibit somewhat diverse properties. A public health emergency of international concern issue by WHO had presented a comparative data analysis of the fatality of these three viruses and had established that SARS-CoV 2 had presented the lowest fatality rate of 2.8%, followed by SARS-CoV with a rate of 9.19% while MERS had presented that highest rate of 34.4%. (Prompetchara, 2020)Research has also identified that SARS-CoV2 had a 94% similarity to the replicase domains in ORD1ab SARS-CoV virus. (Zhouetal., 2020)Not only that, an 88% similarity to two other bat derived-SARS like coronaviruses such as bat-SL-CoVZC45 and bat-SL-CoVZXC21 found in eastern China. This suggests that the novel coronavirus falls between two different types of coronaviruses. (Lu etal., 2020)

The following table had been presented as an overview of the different findings comparing the most recent coronaviruses:

MERS, for example, had presented with aggressive pathogenic effects while the SARS-CoV 2 has been identified to be one of the highly infectious coronaviruses to date.

An analysis of the spike protein found on the surface of the coronaviruses had been established as illustrated by figure (1).

The comparison between the sequences of the receptor binding site had illustrated that there had been an increase in the variability of the Sb ACE 2 binding domains compared to SARS. This can be explained by the evolutionary pressures that are common for most viruses. Another study had also compared the novel SARS-CoV 2 to the genomic characteristics of the SARS-CoV virus, and it had established the following:

An inspection of the amino acid sequences of the receptor binding domain of the spike protein presents 6 critical amino acids for the interactions with the ACE 2 receptor, a common target for both viruses. What has been apparent is that the SARS-CoV 2 does not contain five of these amino acids and yet it still exhibits a higher affinity to the ACE2 receptor compared to SARS-CoV. (ranging from codon 484 to 507, covering five adjacent functional sites: F486, Q493, S494, N501, and Y505) (Tang etal., 2020)

Another novel finding is that the COVID-19 virus has acquired a polybasic cleavage site that is susceptible to cleavage by cellular proteases.

A final factor that leads to the variability of the arising coronaviruses are due to the large size of the genome that can be susceptible to mutations, which lead to diversity of genome.

Infectious Cycle of Coronaviruses

Attachment and Entry

Entry is driven by interactions between the spike protein on the viral surface with the angiotensin converting enzyme receptor (ACE 2). Another cellular surface protein, a protease called TMPRSS2 or cathepsin L facilitates proteic cleavage necessary for the fusion machinery. (Walls etal., 2020)

Two cleavage events have been denoted to the entry mechanism of the SAR-CoV that is suspected to be true for the novel SAR-CoV 2.

Cleavage event #1

This cleavage separates the receptor binding domain of the spike protein from the fusion domain.

Cleavage event #2

This cleavage event activates the fusion domain and promotes fusion of the viral and cellular surfaces.

Research have confirmed that aimed to confirm what entry mechanism is exactly used in SARS-CoV, and it has been confirmed that it enters the cell via endocytosis, at which inhibitors on endosomal lysosomes had been used to test the hypothesis, and results had confirmed that lysosomal proteases are needed to cleave the spike protein to activate the fusion machinery. (Liu, 2016)

Once the fusion domain is activated, the viral genome encapsulated by an endocytic vesicle can either be deposited within the cell by probable mechanisms such as endocytosis or right after fusion of viral and host surfaces (membranes).

Note: But again, this still remains under study for the precise mechanism of proteolytic cleavage of SAR-CoV 2, as well as the specific steps of viral entry which has been reckoned to be another cause of the high viral infectivity. (Mengetal., 2020)

Replication and Genomic Expansion

SARS-CoV 2 genome was annotated to possess 14 open reading frames encoding for an estimation of 27 proteins. RNA virus, once its genome has been deposited within the host’s cell, the ability to translate or generate proteins requires it to follow the “gene expression rules” of the host. And so, for prokaryotes such as RNA viruses, gene expression is usually polycistronic, at which one gene can transcribe and translate different proteins. This is not the case for eukaryotes such as humans, that follow a monocistronic property. It’s also important to highlight that an important characteristic of transcription is the formation of subgenomicmRNA, in which small RNA molecules are formed from the original RNA genome.

A framework of the overall replication cycle is as follows:

Translation of the sense RNA strand of the viral genome occurs with a simultaneous ribosomalframeshifting, producing 2 polypeptides, pp1a and pp1b. Ribosomalframeshifting occurs due to the presence of identical TRS sequences within different parts of the strand. Proteins produced at this stage are utilized for replication and further transcription later on.

Resulting proteins will form a transcriptase and replicase complexes, and will combine with the sense strand and will promote replication. Replication of the sense strand produces an antisense RNA strand that will undergo the two following fates:

It can be replicated once more to form a sense RNA, identical to the original genomic strand.

This antisense strand can be discontinuously transcribed, producing a variety of mRNA that code for different proteins. An important point to consider for the discontinuous transcription is that it is a unique feature of coronaviruses as it entails the high rate of RNA recombinations, that leads to more diversification.

The resulting viral proteins as well as the sense strand produced will be packaged to form a viral progeny that will exit the cell and infect other cells of the body.

Interaction with Host Cells & Immune System

This is still understudy, but possible notions include the same basic framework presented previously of the pathogenic mechanism of action by SARS-CoV. Prompetchara and colleagues had presented an illustrative proposition of the immune mechanism and response involved in the contemporary SARS-CoV 2 that involves cytokine storm, delayed type I IFN response, and sepsis shown in Figure (5):

Figure.6 Viral interaction of SARS-CoV 2 with host Immune system, response and mechanism of (Prompetchara, 2020)

Conclusion

In retrospect, the analysis of the 1918 pandemic showcases that viruses of the same ancestry continue to exist due to the continuous antigenic shifts and drifts. What’s important to reflect on from this comparison is how both the 1918 H1N1 virus and the SARS-CoV 2 are denoted to be out of the norm where the virus's manifestation had resulted in a mass spread of disease internationally, and had radical repercussions. It’s also important to note that we live in a far more globalized world than how it has been during 1918, and other factors such as the environmental changes play a role.

Nonetheless, such pandemics are elements of change, not just change in the medical or scientific basis of human knowledge but these phenomenons are key players in reshaping the social and political aspects of human lives, in a way or another these call for us humans to change. This is a time of reflection upon the past, as well as reshaping what it means to thrive in the future.