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Decoding Covid-19 - The Response

Updated: Aug 30, 2020

In the previous blog, we saw how the virus works its way into our Alveolar cell. Now lets look at how our immune system deals with it.

Before we go to the immune response, lets first look into the common symptoms experienced by the people infected by the virus.

Key Players who partake in the immune response

The Immune Response

Once the virus manages to enter into our lung cells and start replicating, it also releases certain chemicals that damage the alveolar cell. Alveolar cell is where gas exchange takes place. This sets of a chain reaction triggering the following immune response:


The damaged cell releases cytokines which signals other non infected cells to buckle up and get ready for a fight. This will also alert phagocytes (one kind of white blood cells), which upon recognition of an invasion by a pathogen, will bind using its lock (Pattern Recognition Receptor - PRR) to the key (Damaged Associated Molecular Patter - DAMP) of the virus. These patterns are usually specific to the virus (i.e. they are not present in the host and therefore are considered as “non-self” or in other words foreign cells).

Inflammatory Response

Phagocytes (Macrophages) will also trigger the release of chemicals (Cytokines like TNF-Alpha, Interleukin1,6,8 and Chemokines), which signal that a pathogen is present and needs to be destroyed along with any infected cells. These cytokines will stimulate the nerve endings of the lungs initiating the cough response and hence the dry cough.

Interleukin 8 will recruit Neutrophils and Chemokines will recruit other macrophages thereby increasing the WBC cell count. The job of the these phagocytes is to engulf and kill the viruses, however too many neutrophils eventually cause damage to the cell tissues due to the release of Reactive Oxygen Species (ROS). This damage to the alveolar cell wall results in less Surfactant. Surfactant is a molecule that forms a thick layer over the alveolar fluid, which reduces the surface tension in the alveoli. With surfactant, the force produced by surface tension is approximately 3 mm Hg; without surfactant, the force can be as high as 30 mm Hg. Thus, surfactant greatly reduces the tendency of the lungs to collapse.

Due to less surfactant caused by the alveolar cell damage, the lungs (Alveolar cells) start to collapse. This leads to less Oxygen. Chemicals (TNF-Alpha and IL1) released by the macrophages increases vascular permeability making the fluids to seep into the alveolar cell causing pulmonary edema, causing dyspnea (shortness of breath) and hypoxaemia (low concentration of Oxygen). Both of these responses lead to breathlessness.

Damaged endothelial cells release inflammatory mediators (leukotrienes and prostaglandins), which cause bronchoconstriction impairing ventilation leading to more hypoxemia. Decreased O2 levels will stimulate chemo-receptors in the brain, which will in turn stimulate pulmonary centers to signal the heart to beat faster and lungs to breathe more to make up for the falling O2 levels. This leads to tachypnea (more breaths/minute) and tachycardia (more heart beats/minute).

Pro-inflammatory chemicals (cytokines) released by WBCs (neutrophils and macrophages) stimulate the anterior hypothalamus to produce prostaglandins, which lead to an increase in body temperature. Fever is believed to be helpful in eliminating infections because most pathogens grow optimally at temperatures lower than normal body temperature. Fever also causes the liver to withhold iron from the blood. Without iron, certain pathogens are unable to replicate; this is called nutritional immunity.

Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, fatigue, muscle pain (Myalgia), and nausea.

These effects may have evolved because the symptoms encourage the individual

to rest, preventing them from spreading the infection to others.

Cytokine Storm - Collateral Damage

In addition to being released by phagocytes after DAMP recognition, cytokines (Interleukins) are also released by the infected cells which bind to nearby uninfected cells, inducing those cells to release cytokines as well, resulting in a cytokine burst. Its a bit like a fire alarm that never stops, which leads to firemen showing up on your doorstep over and over. Now imagine firemen having to break through stuff or cause damage on their way in. This is pretty much what happens inside our body when the cytokine signalling does not stop. If the attack by the virus is relentless and our very own immune system is super strong, a severe local tussle ensues, turning the cytokine burst into a cytokine storm causing local inflammation and cell damage. Elevated levels of cytokines and other immune molecules are associated with these storms.

Our immunity is pretty much a double edged sword. The very thing that is enlisted to protect us can end up harming us if it is not kept in check. It is the severe excessive immune response caused by a positive feedback cycle between cytokines and immune cells, which leads to elevated levels of pro-inflammatory cytokines and anti-inflammatory cytokines in the serum and it is this fierce, often lethal interplay of these cytokines that leads to the 'Cytokine Storm', which if not addressed can lead to Acute Respiratory Distress Syndrome (ARDS), Pneumonia because of the damage caused to the lungs due to accumulation of fluids (increased permeability), ventilation/perfusion mismatch (less surfactant) and hypoxemia that is not related to heart function . This will eventually lead to multiple organ failure and is one of the leading causes of mortality in Covid-19.

Adaptive Immune Response

Our adaptive immune response is staged by:

B cells, which make antibodies and signaling proteins that help to flag or attack invading bacteria, viruses, and toxins.

We can synthesize large amounts of specific antibody against virtually any foreign determinant

within a matter of days of being exposed to it so our immune system is pretty bad ass!!

T cells, on the other hand, do not secrete antibodies but performs a variety of functions in the adaptive immune response. Different T cell types have the ability to either secrete soluble factors that communicate with other cells of the adaptive immune response or destroy cells infected with intracellular pathogens.

Upon recognition of an invasion by the virus, phagocytes (Neutrophils, Macrophages and Dendritic cells) will bind using its Toll Like Receptors (one type of PRR - locks) to the DAMP (key) of the virus. They will then engulf the virus and partially degrade it, and export fragments (antigens) of the virus to the cell surface, where they are presented in association with MHC II molecules on its surface, like a wanted poster sending signals that a virus is present and needs to be destroyed along with any infected cells. A receptor on the surface of the helper T Cell then binds to the MHC-Antigen complex, which will initiate the Adaptive Immune Response.

The activated Helper T Cell (TH2) releases cytokines, which will in-turn stimulate B Cells. Cytokines stimulate the infected cells and those nearby to produce proteins that prevent the virus from replicating within them. Cytokines released by TH1, In particular, gamma interferon greatly increases the ability of macrophages to kill ingested viruses; this can tip the balance against viruses that otherwise resist killing. Gamma interferon also stimulates natural killer cells,

Natural Killer and Cytotoxic T cells, which respond to interferons released by the infected cell can kill their target cells either through the use of pore-forming molecules, such as perforins (which literally put holes in the cells) and various components of cytoplasmic granules, or non granular cytotoxic T cells by triggering a series of events with the target cell that activate cell death program, a process called apoptosis. Interferons signal neighbouring infected cells to undergo apoptosis (programmed cell death).

So the target cells pretty much sacrifice themselves for the greater good by

committing suicide, thereby destroying the virus within the cell as well.

Cytokines secreted by cytotoxic T Cells stimulate B cells, that will further divide into plasma cells, which are responsible for releasing antibodies and memory cells, which keeps a record of the encountered pathogen and forms part of our long term immunity. However memory cells have a shelf life and we lose some of this immunity over the course of time if we are not exposed to the pathogens again.

B cells are manufactured with random receptor shapes in hopes that any pathogen we may encounter will have a matching B cell. Statisticians argue that the chances of us having a match are so astronomically high that it’s safe to say there’s one in our body somewhere. The problem

is finding it before the pathogen does irreversible damage.

Our immune system is constantly working hard to keep us safe from the pathogens. All three defense and attack systems like the physical barriers, innate and adaptive immune systems work together to keep pathogens out. All three systems work together to keep us safe and build our immunity through memory cells so we are all well prepared if we encounter the same pathogen again.

Now we know how our immune system responds to the corona virus and the collateral damage that is caused in the process. So why is that this virus seem to effect a certain segment of the population the most, is lockdown the right approach? these and other myths dispelled in the next blog.

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