The current global pandemic caused by novel coronavirus- COVID-19, first emerged in Wuhan, China back in December 2019 and is believed to be zoonotic in origin. Since then it has swept over the planet and caused over 200,000 deaths as of April. Since the outbreak first began, the genome has been sequenced but no vaccine has yet been developed.
A team in Wuhan studied a 41-year-old patient who worked at an indoor seafood market and was hospitalised 6 days after the initial onset of the disease. They were able to sequence the viral genetic code and it was found that COVID-19 belongs to the genus beta-coronavirus and subsequently shares 89.1% of its nucleotide sequence with SARS-CoV. This means the method of how the virus replicates can be concluded due to similarities between the two viruses and how they both enter the body in the same way. COVID-19 is a beta-corona virus consisting of a single strand of positive RNA enclosed in a lipid bilayer which is transmitted person-to-person primarily through direct contact and droplet transmission through coughing or sneezing from an individual infected with the virus and has an incubation period of 2-14 days.
The virus then enters the lungs into the alveoli where Wrapp, D et al found that the virus enters the lung epithelial cell through binding between the angiotensin-converting enzyme 2 (ACE2) receptor and the receptor-binding domain of the virus glycoprotein spikes, just as SARS-Cov does. However, COVID-19 has a greater affinity for the receptor than SARS-CoV which explains its high pathogenicity. Without the spike (S) proteins or the ACE2 receptor the virus cannot enter the cell and therefore cannot infect the body. The virus enters to the cell cytoplasm through acid-dependent proteolytic cleavage of the spike (S) protein by a cathepsin or another protease. This cleavage exposes a fusion peptide that inserts into the membrane and is followed by two heptad repeats in the S protein which form an antiparallel six-helix bundle which allows the viral and cellular membrane to fuse and release the viral genome into the cytoplasm.
The original team in Wuhan consisting of Wu, F et al found that the virus genome consists of a single strand of positive RNA, where the viral RNA then binds to a free cytosolic ribosome and the replicase gene is translated. The replicase gene contains two open reading frames- rep1a and rep1b and they express two co-terminal polyproteins- pp1a and pp1ab respectively. To ensure that both polyproteins are expressed correctly the virus uses an RNA pseudoknot as seen in Figure 1 which consist of two helical segments connected by single stranded regions or loops causing a frameshift of one nucleotide until the ribosome is able to move through the pseudoknot and continue translation to produce RNA replicase. After translation of the RNA the two polyproteins are then cleaved into their individual non-structural proteins which assemble into the replicase-transcriptase complex so that RNA translation can occur. The
synthesis of new RNA through negative-strand intermediates produces sub-genomic RNAs that act as mRNAs for the genes downstream of the replicase gene, as well producing as genomic RNAs.
COVID-19 consists of four main structural proteins . The spike (s) protein as well as membrane (M), envelope (E), and nucleocapsid (N) proteins as shown in Figure 2 . After replication occurs of the viral RNA, the structural proteins of spike (S), envelope (E) and membrane (M) are translated and transported to the host endoplasmic reticulum where they are processed with as any host primary sequence of amino acids would be. This involves the 3 proteins moving along the secretory pathway from the endoplasmic reticulum into the Golgi apparatus intermediate compartment where the viral genomes are formed into a capsule by the N protein and bud off into membranes containing the structural proteins and form the mature virions.
Expression of the membrane (M) protein is what controls most of the interactions between both structural and non-structural proteins that are required for the assembly of the full coronavirus- but require the expression of envelope (E) proteins alongside in order for virus-like-particles to form. The fusion of encapsulated genomes from the endoplasmic-reticulum-golgi apparatus intermediate compartment mediated by the nucleocapsid (N) protein enhances the virus-like-particle showing that the N protein further enhances viral development. As well as the encapsulated genome binding to the nucleocapsid, the C-terminus of the membrane (M) protein also binds to the c-terminal domain of the nucleocapsid, which causes the virion to become fully assembled.
The fully assembled virions containing only positive-sense full length genomes are transported to the cell plasma membrane in secretory vesicles and from here are released by exocytosis where they go on to bind to host cells and enter by endocytosis without being detected as foreign RNA as the nucleotides forming the RNA are that of the host. The virus is able to spread through the host without being detected or neutralised by the hosts defence system of antibodies