The coronavirus is causing a major worldwide pandemic. It has spread from the epicentre in Wuhan, China to all over the world affecting 213 countries and territories. Only 12 countries have yet to report any cases of the deadly virus. The virus itself is a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and causes Coronavirus disease 2019 (COVID-19). The key reservoir of the virus was found to be bats as the virus has a genome that shows 96.2% similarity to that of the bat CoV RaTG13.
So, what exactly is the novel coronavirus?
Coronaviruses are the largest group of viruses in the order known as Nidovirales. They belong to the Coronaviridae family. Specifically, SARS-CoV-2 is in the Orthocoronaviridae subfamily – a b-coronavirus. This type of coronavirus is an enveloped, single-stranded, non-segmented positive-sense RNA virus, with crown-like spikes on the outer envelope. Their genome is 29.9kb. SARS-CoV-2 has 4 main structural proteins: spike (S) glycoprotein, these form homotrimers protruding in the viral surface and facilitate binding to proteins expressed on the lower respiratory tract cells; membrane (M) glycoprotein, this can bind to all other structural proteins and stabilise the nucleocapsid; nucleocapsid (N) protein, this is bound to the viral RNA thus is used for processes associated with the viral genome. It is also largely phosphorylated which suggests it undergoes structural changes and influences the affinity for viral RNA; small envelope (E) glycoprotein, this plays a role in the production and maturation of the virus.
How does the coronavirus replicate?
The replication cycle of the virus begins by transmission and infection of the human respiratory tract. It is primarily spread through respiratory droplets and contact routes. Once it has reached the cells of the respiratory tract, those that express the protein angiotensin-converting enzyme 2 (ACE2) allow the S glycoprotein to attach to it stimulating fusion between the host cell and the virus membrane. Cells that express ACE2 that are found in the respiratory tract include the nasal epithelial cells such as goblet/secretory cells, ciliated cells and type II pneumocytes. When fusion occurs, ACE2 is cleared by the type II transmembrane serine protease causing a conformational change allowing viral entry.
Once in the cell, the positive-sense RNA can be directly translated into viral proteins. The SARS-CoV-2 genome has 14 open reading frames. Non-structural polyproteins are primarily translated known as pp1a and pp1ab. These are subsequently cleaved by protease enzymes mainly papain-like proteases and a chymotrypsin-like protease into the non-structural proteins 1-11 and 1-16 respectively. Many of the translated non-structural proteins form replicase-transcriptase complexes in double membranes vesicles that allow the production of negative-sense RNA, then more positive-sense RNA. Secondly, the structural and accessory proteins are translated. These are insulated in the endoplasmic reticulum and transported to the endoplasmic reticulum-Golgi intermediate compartment – a collection of tubulovesicular membrane clusters facilitating transport between the endoplasmic reticulum and Golgi apparatus. The replicated genome binds to the N protein and also moves into the endoplasmic reticulum-Golgi apparatus intermediate compartment. Here, the structural and non-structural proteins gather and form small vesicles. These vesicles are ready to undergo exocytosis and infect other respiratory cells.
How does the virus affect the immune system?
When the virus infects the host cells, it triggers an immune response. Firstly, the innate immune response is activated which mainly involves dendritic cells and alveolar macrophages. Such cells use pattern recognition receptors including Toll-like receptor 4 (TLR-4), which is thought to recognise the protein spike of SARS-CoV-2, endosomal TLR-3 and TLR that can recognise viral RNA. These receptors recognise pathogen-associated molecular patterns displayed by infected and apoptotic host cells. TLR-4 activation leads to NF-κB and MAPK activation responsible for an increase in pro-inflammatory cytokine and chemokine expression – TNF-α, IL-1, IL-6, IL-12, and CXCL10. Activation of TLR-3 and TLR causes the adaptor protein TRIF to be recruited which increases NF-κB expression and production of pro-inflammatory cytokines IFN-α and TNF-β. However, long-term expression of these pro-inflammatory proteins leads to acute respiratory distress syndrome – a clinical symptom of COVID-19. Antigen-presenting cells then activate the adaptive immune cells – CD4+, CD8+ cells, and NK cells. In severe conditions, aberrant pathogenic CD4+ T cells that co-express IFN-γ and GM-CSF are present. Although GM-CSF is used to help differentiate innate immune cells and increase T cell function, it has been found to cause tissue damage in large concentrations like that present in the lungs seen in COVID-19. Overall, an increase in immune cell activation and recruitment is an attempt to rid the host of the virus, however, an overactivation can lead to tissue damage due to a collateral effect of the immune cells. A cytokine storm, for example, can cause tissue damage at the site of infection and even lead to organ damage away from the lungs.
Why do different people experience different severities of COVID-19?
The overall effect of coronavirus on a patient varies. So, why do some people get a more severe form of COVID-19? That all depends on any pre-existing medical conditions of the patient like diabetes, heart disease and hypertension, smoking and other factors such as age and genetics.
Diabetes mellitus is a disease that results in abnormal blood glucose levels. It is suspected to be linked to the severity of COVID-19. In type II diabetes, studies have shown that there is an NK cell dysregulation. Sufferers have a reduced amount of NKp46- and NKG2D-positive NK cells, as well as defects in NK cell function – those who had uncontrolled diabetes, had the lowest NKG2D expression. This increases the severity of COVID-19 in these patients as NK cells are the key immune cells for dealing with viral infections. A lower frequency of NK cells means the patient’s immune response will be weaker, allowing the virus to infect more cells over a longer period of time resulting in larger tissue damage.
Heart disease and hypertension are disorders of the heart but their conditions can be exacerbated by an infection with the novel coronavirus. The heart cells also express the protein ACE2. Consequently, scientists believe that the virus can infect heart cells like they infect respiratory cells. ACE2 has anti-inflammatory roles and serves to reduce the damage on the body’s own cells from immune cell recruitment and action. When the virus binds to ACE2, the receptor’s function is impaired reducing the anti-inflammatory function. For example, a cytokine storm would more likely occur due to the impairment of ACE2 thus damaging tissues and causing further complications. It is also believed that the virus disrupts efficient blood transport around the body by affecting the heart. Therefore, a patient with cardiovascular disorders will be faced with greater consequences and strains due to the infection.
Smoking is thought to exacerbate COVID-19 due to its effect on the respiratory cells. Research has been geared towards understanding how this occurs. One thought is that there is an increase in ACE2 expression in smokers. One study found that smokers had 40%-50% more ACE2 expression than non-smokers. This is due to the increased number of goblet cells that appear in the respiratory tract in smokers, particularly in the lower respiratory tract. As a result, smokers are left more prone to SARS-CoV-2 infection by an increased expression of the receptor that acts as a doorway for the virus. Not only this, but smokers also face many comorbidities that impair the function of the healthy lung and the ability to fight off an infection – emphysema and a compromised immune system being the most common. Chronic inflammation, a weakened immune system, and tissue damage all act as an army for coronavirus to help destroy the host cells and cause a more severe form of COVID-19.
Age also plays a role in differentiating between a severe and potentially fatal form of COVID-19 as oppose to an asymptomatic form of the disease. In the US, 8 out of 10 deaths are associated with adults over 65. The main reason for this is because older people suffer from more chronic medical conditions that amplify the effects of the infection such as heart disease and hypertension. The immune system is also less effective as we age. Its ability to deal with pathogens declines over time leaving older people more vulnerable to the virus and at a greater risk of symptoms that are far worse than the average infected person.
Genetic factors have also been thought to link to the severity of the disease. Many healthy, young individuals have seen severe and sometimes fatal effects of the coronavirus which led scientists to believe vulnerabilities may be found in our own genetic code. The research is relatively new and ongoing into the specific genetic factors but speculation around ACE2 genes and their relation to the specific structure of the ACE2 receptor have been investigated to see if changes in structure affect the ability of the virus to infect the ACE2-expressing cells. Secondly, genetic variability in HLA genes may play a role in susceptibility and severity of COVID-19. Research around this topic found that individuals with allele HLA-B*46:01 were more at risk of severe COVID-19 than others.
Why is knowing all of this so important?
The novel coronavirus has proven to be a deadly wake-up call that the world needs. Although we have seen many versions of coronavirus, we could never have been prepared for that of SARS-CoV-2. Its accessory genome has made it difficult for scientists to help find an efficient vaccine or treatment to help stop the spread of the virus and help reduce the effect of the outbreak. It is useful to understand how the virus replicates inside of the human body as this acts as a window of opportunities to investigate and attempt to produce the necessary therapeutics to treat the infection. Further information about how the virus works will allow further breakthroughs that will change the course of the pandemic, driving it towards a brighter future and allowing us to be better prepared for a second outbreak.
Comments