COVID-19: What happens inside you?

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Several health facilities in China reporting pneumonia of unknown origin around late December 2019 was the first sign of impending danger. These cases were traced down to the animal market in Wuhan, China and sequencing found the cause to be a virus of the genus betacoronavirus, later named SARS-CoV-2 and the disease as COVID-19. It grew at an alarming rate to be declared a pandemic on March 11, 2020 by WHO. As of April 29, 2020, COVID-19 has claimed 207,973 lives from over 3.018 million cases and the curve seems far from being ‘flattened’. Compared to SARS and MERS epidemics with fatality rates of 9.5% and 34.4% respectively, COVID-19 is far less deadly with a crude fatality rate of 6.8% but each infected person infects many more people, doubling the total number of cases in 2-3 days without intervention; compared to SARS or MERS which took twice the number of days to double.

But what happens when the virus infects a human cell? To understand this, let us first look at the structure of the virus particle, called a virion, and the proteins that enable it to enter a cell.

Structure of the SARS-CoV-2 virion

A SARS-CoV-2 virus particle is spherical and measures around 50-200 nanometres in diameter (one nanometre is a billionth of a metre). Like other viruses it carries genetic material that has all the information for the virus to infect the preferred host cell and replicate itself. Its genome is a single molecule of RNA that is made of around 30,000 nucleotides that can directly code up to 29 proteins. Among these are structural proteins including Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N). These proteins constitute the virion body, guide it to the target host cells and protect the viral genome. The remaining viral proteins are nonstructural and accessory, which are made in infected cells and help in hijacking the host cell machinery.

Replication cycle of SARS-CoV-2

The virus life cycle involves three major stages: entry, replication and exit. The virus recognizes the target cell, hooks onto it, and then enters and releases its RNA inside the cell. Next, the virus hijacks the cellular machinery to produce copies of its genome and proteins. Finally, new virus particles assemble and come out of the host cell to infect neighbouring healthy cells.

How the virus enters a cell

The virion enters the body of a healthy individual directly in the form of respiratory droplets through eyes, mouth, and nose or indirectly via contaminated surfaces. Once in the body, the virus travels down from your nose to your windpipe (trachea) and enters your lungs, where the windpipe branches into two tubes called bronchi and further into finer tubules called bronchioles. At the end of each bronchiole is a balloon-like sac called alveolus that is the site of exchange of gases (O2 and CO2). Each lung contains around a million alveoli. The virus infects a specific type of cell in alveoli and bronchi called type II pneumocytes or type II alveolar epithelial cells.
 

 

A type II pneumocyte, like other kinds of cells, expresses a variety of proteins on its surface, which perform a range of functions essential for the cell’s survival. However, a few of these surface proteins may serve as the “key” for viruses to enter a cell. The SARS-CoV-2 virus recognizes and binds to one such protein called Angiotensin Converting Enzyme 2 (ACE2) with the help of its Spike (S) protein. The S protein of the virus comprises two functional subunits: S1, which helps in identifying the correct receptor and then facilitates the correct posture to make contact, and S2, which facilitates fusion of the viral and cellular membranes.

To enter a cell, a virion needs to activate its spike protein, and this requires its scission by a few cellular protein scissors like TMPRSS2 or Cathepsins. Once the S protein is activated, the virus can enter the cell by fusing with the cell membrane and releasing its RNA into the cell cytoplasm or via the cell's feeding mechanism called endocytosis. Camostat mesylate is a drug that is an inhibitor of these protein scissors, and is hence therapeutically promising in treating COVID-19.

How the virus replicates inside a cell

Once inside the cytoplasm of a cell, the viral RNA hijacks the host cell’s protein-synthesizing machinery to synthesize its own chain of many proteins, called replicase polyprotein. This huge chain is then cleaved by protein-digesting enzymes of the virus into individual proteins called non-structural proteins. One of these non-structural proteins now functions as a RNA copying machine (RdRP), which produces multiple copies of the viral RNA using the host cell’s resources. This RNA copying machine sometimes makes errors (mutations) while copying, eventually helping the virus to change its features and emerge as a new virus that the body has never encountered before, leaving the human body vulnerable for a new infection. RdRP is a potential drug target and its function can be blocked by certain drugs like Remdesivir and Arbidol.
The structural proteins S, M and E are also synthesized and assembled along with the replicated viral RNA that is then released. The millions of new virion particles then infect other healthy cells in the lungs. The host cell looks like a virus-producing factory under the control of the virus that infected and hijacked it.
 

 

Now that we know how exactly a virus enters our body and produces many copies of itself, let's see how the body responds to these events and how symptoms of COVID-19 begin to appear.

How the body’s immune system responds

The presence of any foreign DNA/RNA/protein molecule within a cell is detected by certain sensors. They relay this information to the cell’s nucleus to activate a response in order to eliminate the foreign invaders. In case of SARS-CoV-2 infection, the viral RNA is recognized by one or a few RNA sensors, like RIG-I/MDA-5, that then begins a cascade or downstream signaling process, ultimately leading to the production of a group of signaling proteins called interferons.
 

Interferons are released by the infected cells, and act on nearby cells to warn them of the danger. This acts as a signal for them to produce various proteins and factors that interfere with the viral life cycle. The infected cells, under the influence of interferons, also secrete many small chemical messengers, called cytokines. The cytokines diffuse into the blood and attract a large number of white blood cells (WBCs) that can fight the infection in the lungs. Some of the WBCs do so by engulfing the virus-infected cells, while others produce certain proteins, called antibodies. The antibodies can specifically bind to the viral protein against which it has been produced. For example, an anti-S protein antibody will bind specifically to the S-protein of the virus, making it incapable of attaching to the ACE2 receptor on new healthy cells. These antibodies are therefore called neutralizing antibodies.
 

Cytokines also act as a signal to the temperature-regulating centers inside the brain (hypothalamus) to raise the body temperature. Thus, a COVID-19 patient experiences fever during the infection.
 

As the virus-infected cells in the lungs are killed by WBCs, the lung tissues suffer great damage, leading to accumulation of fluid in alveoli. This leads to a loss of surface area for exchange of gases, and the patient therefore experiences coughing and shortness of breath, a condition known as Acute Respiratory Distress Syndrome.
 

All this manifests in the form of the common clinical symptoms of COVID-19, including fever, cough, fatigue, sputum production, shortness of breath, sore throat, headaches and in some cases, diarrhoea and vomiting. Analysing these symptoms along with data obtained from other tests like qPCR (to check for genetic material of virus from patient samples) or ELISA (to check for antibodies made by the immune system against the virus) is used for diagnosis.

What happens when the immune system overreacts

In a healthy individual, the immune responses should ideally lead to resolving of the infection in 6 to 8 days. However, people who suffer comorbidities – like diabetes, hypertension, HIV, cancer, autoimmune disorders, heart-related disorders or someone who had a transplant and is on immunosuppressive medications – face more severe symptoms. In such patients, the immune system becomes overwhelmed and sometimes overreacts to the viral infection. The exaggerated immune response causes a surge in the numbers of activated WBCs that migrate to the lungs and causes lung injury, called immune-induced lung pathology, followed by fluid build-up in alveoli. This causes severe pneumonia and the patient needs life-supporting systems like a ventilator to breathe. At the same time the body suffers a cytokine storm due to excessive amounts of cytokines released by hyperactive immune cells. This negatively affects many organs in the body, like kidneys, liver, and heart. At this point, the immune system becomes really exhausted and vulnerable. Many opportunistic secondary bacterial infections can now invade the body and worsen the condition. These bacterial infections, which are otherwise non-lethal, spread throughout the body and cause septic shock. This sequence of events could lead to multiple organ failure and the patient can succumb to the disease.
 

With nations under lockdown and brave people working around the clock to keep the economy running, the COVID-19 pandemic has taken a heavy toll on life everywhere. A lot of information about SARS-CoV-2 still lies in uncharted territory. Host immune system relations of the virus with respect to evasion, antagonism and cross-reactivity with other coronaviruses is yet to be understood and could lead to extended therapeutic options. Despite attempts to come up with vaccines, mutations and emergence of novel virulent strains can lead to bottlenecks in the pipeline and research should go into exploring the same. Whether SARS-CoV-2 infections take up seasonal patterns like influenza is another question of utmost concern. Only active research can shed light on what time has in store for the worst pandemic to hit us in recent times.