By Poorvaja Chandramouli
The Depths of Covid-19
Since the start of the 21st century, three distinct coronaviruses have evolved, each causing deadly pneumonia in humans. The latter of the three, severe acute respiratory coronavirus 2 (SARS-COV-2), is the cause of the coronavirus disease, COVID-19. Branching out as an epidemic, it has now spread worldwide morphing into a global pandemic.
The unpredictable nature of SARS-COV-2 is seen with its broad spectrum of symptoms ranging from asymptomatic carriers to individuals experiencing flu-like symptoms such as fever, cough, dyspnea to acute respiratory distress syndrome ARDS, the main cause of death. The severe cases of COVID-19 include patients having the progressive pathway to multiple organ failures including the kidneys, heart, liver, and gastrointestinal tract. SARS-COV-2 is seen to affect older adults and others with underlying medical conditions like heart or lung disease or even diabetics.
SARS-COV-2 spreads from person to person via infected respiratory droplets generated through coughing, sneezing, or talking. These respiratory droplets can stay in the air for up to three hours and on surfaces for 24 hours. COVID-19’s R0, “R naught value,” between 2 and 3.3 is greater than influenza accounting for the rapid transmission. Within SARS-COV-2 hides the instructions for its abilities, behaviors, and functionalities leading scientists to investigate and counterattack.
Genotype/Phenotype Description of Covid-19
The identification of any organism in the world can be extracted from its instruction manual used to code for its unique phenotypic characteristics. Viruses unlike humans consist of either DNA or RNA within themselves. SARS-COV-2 is an enveloped virus holding a positive sense single stranded RNA genome. Positive sense viral RNA indicates that the sequence will directly translate into its viral proteins. The RNA in SARS-COV-2 has a 5’methylated cap and a 3’ polyadenylated tail. This attribute is fortunate for the virus because it mimics the structure of a host mRNA. Compared to other RNA viruses, coronaviruses possess the longest genomes. Approximately the length of SARS-COV-2’s genome consists of less than 30,000 nucleotide bases. The genome has the instructions to code for both the structural and non-structural proteins that make up the virus.
As the machinery found in the host cell, the ribosome, begins translation with the first two thirds of the genome being 2 large overlapping open reading frames (ORFs). ORFs are a stretch of nucleotide sequences containing an initiation point of translation and a termination point of translation read by the ribosomes. The first two ORFs, ORF1a and ORF1b, are found near the 5’ end of SARS-COV-2 encoding for the replicase polyproteins 1a (PP1a) and 1ab (PP1ab). The largest of these polyproteins, PP1ab, cleaves itself to form the 16 nonstructural proteins which help form the viral replicase transcriptase complex. These include proteases, RNA-dependent RNA polymerase, etc. These 16 viral subunits and a number of other cellular proteins are used in the host cell to help propagate new viral mRNAS to include in the virion.
Progressing further down the next third of the genome, located towards the 3’ end, the remaining ORFs can be found. In SARS-COV-2’s genome there has to be certain ORF’s necessary for encoding the proteins appearing on the surface of the virus. The nucleotide bases within the ORFs create four major structural proteins occurring in the 5’-3’ order S (Spike protein), E (Envelope protein), M (Membrane protein, and N (Nucleocapsid protein). These proteins combine together to form the phenotypic structure of SARS-COV-2. These are adaptations that give the virus its identity and in the case of the spike protein allow it to easily slip through the host cell membrane. In the production of these proteins through translation, many serve to hijack the cell processes and tell the cell to divert its attention and energy towards virus production only.
Scientists and other medical health professionals are dedicating their research of the virus towards understanding the genome of SARS-COV-2. The genome sequencing of the virus can tell not only what kinds of proteins the virus codes for but also what parts of the genome account for the corresponding protein. The virus’ phenotypic structures correlate directly with the familiarity with the genome itself.
Structural and Functional Levels of Covid-19
Each virus in the coronavirus family has protruding spikes on the surface giving the appearance of a crown. A large number of spike glycoproteins wrap the surface of SARS-COV-2 and allow the virus to attach to the host cell receptor angiotensin-converting enzyme 2 (ACE2). This receptor is present on the outside of cells in many tissues and is responsible for controlling blood pressure. In the lungs, ACE2 can be found most prominently on the surface of epithelial cells and the type II alveolar cells. Similarly, it can also be found in other major organs such as the heart, kidneys, and intestines. The spike protein is composed of 2 functional subunits. The S1 subunit has the function of binding to the host cell receptor. It contains the receptor-binding domain (RBD) which binds to the peptidase domain of the ACE2 receptor. Whereas the S2 subunit mediates the fusion of both the viral and host’s cellular membranes. This protein binds with the receptor with at least 20 times greater affinity than SARS-COV. Due to the critical role this protein plays, it is a particular focus in the design of vaccines for COVID-19.
Along with the spike proteins the membrane proteins and envelope proteins help to form the structure of the viral envelope. The M, membrane protein, is the most abundant structural protein on the viral surface. It defines the shape of the viral envelope and is regarded as the central organizer of coronavirus assembly. Towards the end of replication, this protein sorts all the viral components in order to be incorporated into the virion. In addition, the membrane protein interacts with all the other structural proteins. The E, envelope protein, is the smallest of the major structural proteins on the viral membrane. As the membrane and envelope proteins interact together, they help form the viral envelope. During the replication cycle of the virus, the envelope protein is found abundant in the host cell but only a small portion of it is incorporated in the virion envelope. Finally, the N, nucleocapsid protein, is different from the other major structural proteins. It is the only protein that operates to bind to the SARS-COV-2’s RNA genome creating the nucleocapsid. This protein is involved in all the processes relating to the viral genome and even the replication cycle.
The SARS-COV-2’s primary function is to access a host cell and replicate in order for its species to survive. Since COVID-19 is a respiratory virus, it infects the respiratory tract including areas such as the nose and lungs. SARS-COV-2 is able to get further into the respiratory tract by
getting down into the epithelial cells of the lungs. As the SARS-COV-2’s spike proteins attach to the ACE2 receptor the transmembrane protease serine 2 (TMPRSS2) activates and cleaves the spike protein. This allows SARS-COV-2 to enter into the host cell through endocytosis or through direct fusion of the viral envelope with the host membrane. The viral genome is released to be translated by the host ribosome into the proteins necessary for the replication transcriptase complex. This complex helps to generate a new RNA genome for the virion. Sub genomic RNAs specifically code for the structural proteins of the virus. The structural proteins are then combined along with the nucleocapsid to form a new virion. These virions are discharged from the infected cell by exocytosis. This replication can occur wherever an ACE2 receptor is present.
The alveoli are a tiny air sac responsible for exchange of oxygen and carbon dioxide between the bloodstream and air. SARS-COV-2 primarily targets the type II alveolar cells found within the alveolus. These cells are responsible for secreting surfactant which reduces surface tension and keeps the space free from fluid. ACE2 is found on these cells which SARS-COV-2 utilizes to replicate into millions of viruses within the alveolus. The damaged alveolar cells can possibly burst, forming inflammatory mediators such as cytokines. The cytokines release into the surrounding bloodstream increasing the permeability. The fluid of the blood, plasma, exits and fills the barrier between the bloodstream and the alveoli where gas exchange occurs. The deprivation of oxygen to the organs leads to ARDS. Eventually the pressure created by the excessive fluids starts to build up against the alveoli compressing it. Since ACE2 is found in multiple regions of the body the corresponding location correlates with the symptoms related when SARS-COV-2 infects it. SARS-COV-2 functions differently in different areas and leads to different outcomes in the body.
Origins
A common theme present in all coronaviruses is that they primarily infect both humans and vertebrates. In relation to taxonomy, the coronaviruses are part of the order, Nidovirales, members of the family, Coronaviridae in the subfamily, Cornavirinae. There are four distinct genus groups split including the Alpha coronavirus, Beta coronavirus, Gamma coronavirus, and Delta coronavirus. Within the Beta coronavirus genus lies the three notorious coronaviruses SARS
COV, MERS-COV, and SARS-COV-2.
The novel coronavirus had originally risen in people inhabiting the city of Wuhan, China. According to a medical journal, The Lancet, first patients described with the coronavirus symptoms fell ill had no contact with the Wuhan wet market. This gives the conclusion that the Wuhan wet market may have been an accelerator for the spread of the virus but not necessarily the origin.
There have been conclusions towards SARS-COV-2 being a handmade virus in the laboratory. Research gives irrefutable evidence that the virus is a product of nature. Scientists have mapped the genomes of over 70,000 samples of SARS-COV-2 from patients in the United States, China, Europe, Brazil, and South Africa. The sequencing has revealed that SARS-COV-2 is 96% similar to the genome of a bat virus called RATG13. Other parts of SARS-COV-2 such as the RBD of the spike protein genetically relate to a coronavirus that infects pangolins. Transmission from bats to intermediate hosts and finally to humans requires the virus to slightly change its genome sequence to improve fitness within the new host. This leads to the belief that the virus is a recombinant of two different species. COVID-19 isn’t confirmed yet whether it is a zoonotic disease or not.
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