Friday, June 19, 2020

Ch 5. A storm is coming - immunity to coronaviruses in context of COVID-19

What will this section talk about?
Cytokine storm, a hyper-immune reaction that can cause damage.

Readability grade 7
Reading time approximately 4:25 minutes

In the previous sections we have seen two possible outcomes. One, seen in majority of cases, is an appropriate immune response which eliminates the virus (Chapter 4). The other, if there is no or poor immune response to virus infection, virus overwhelms quickly causing death (Chapter 2). There is a third possible outcome which has gotten much attention and can also be problematic. This is an intense immune response to the virus called "cytokine storm", and damages organs. These outcomes are represented in figure below
Outcomes depending on immune response to virus infection

What other conditions can cytokine storm happen in?
The cytokine storm is an excessive and uncontrolled immune response. The abnormal immune response damages the health of the host and can lead to death. Besides COVID-19, it is also seen in other medical conditions. These other conditions can be other infections or non-infectious. Reports suggest that even some medications can be cause of cytokine storm. At the heart of the “cytokine storm”, are powerful chemicals called cytokines.

What do cytokines do?
The cells of immune system make cytokines for help with immune response. For example, an early immune cell will communicate with helper cell (Chapter 3) by cytokines. This signal may say to helper cell that infection is bacterial. The helper cells then, through different cytokines inform others (B-cells) to make antibodies. Thus, in the simplest of terms, cytokines are language, a communication between immune cells. Every unique immune cell type has its ability to signal and relaying it forward. A cytokine "storm" then is an excessive chaotic communication. This leads to hyper-activation and damage from this uncontrolled immune activity.

Are there different types of cytokines?
There are 5 major types of cytokines based on their function.
1. Some regulate early immune response, have anti-virus properties. (Interferons, discussed in Chapter 1)
2. Some promote inflammation. (Interleukins)
3. Some help direct movement of immune cells (Chemokines).
4. Some help different types of immune cells grow and survive (stimulating factors).
5. Some cause direct damage to diseased cells. A virus infected cell or cancer cells are examples. (tumor necrosis factor).

How does a cytokine storm start?
The start of a cytokine storm is local inflammation spilling over into the rest of the body. This happens by spreading of the immune cells and cytokines through blood. Many are familiar with the symptoms of local inflammation. For example, a local infection such an abscess or boil causes the affected part feels 1. Warm, there is 2. Redness, 3. Pain, 4. Swelling, and 5. Loss or reduced function. All 5 effects are results of immune system trying to remove the threat of local infection

How does a cytokine storm damage tissue?
In a rapid infection or an overstimulated immune system, the effects occur all over the body. Factors responsible for local symptoms spill over into other organs via blood. The lung and kidneys due to their high blood flows are at high risk from damage. Sepsis, a condition of excessive immune response to blood stream infection, is similar. In COVID-19, the lung gets affected three times. First, from infection of the virus in lung cells. Second, from immune response to kill the virus infected lung cells. Third, if cytokine storm occurs, immune damage to lung. This may be a basis for the severe and sudden cause of respiratory failure in COVID-19.

How common is a cytokine storm?
Cytokine storm is a less common outcome even in COVID-19 infection. Not every one will end up with a cytokine storm outcome. Evidence suggests genetic factors could increase or decrease the risk developing cytokine storm. These genetic differences are in genes responsible for “danger signal” detection (Chapter 1 and Chapter 3) , or cytokine production.

How can a cytokine storm be treated?
At present most treatment is symptom based. The goal of treatment for cytokine storm is to support vital organs like circulation (heart pump machine), respiratory (ventilators), kidneys (dialysis) etc until body recovers. Some medications like dexamethasone are corticosteroids (commonly known as steroids) and have shown benefit by calming down inflammation from over active immune system. Other medications to block cytokines are also available but their benefit is not clear.

Previous section: Ch 4. A favorable outcome - immunity to coronaviruses in context of COVID-19
Next Section: Ch 6. Candidate treatments for COVID-19 infection
List of all chapters 

Reference
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev.. 2012 Mar 1;76(1):16-32.

Tuesday, June 16, 2020

Ch 4. A favorable outcome - immunity to coronaviruses in context of COVID-19

Reading time: approx 3:29 minutes
Readability: Grade 8

Today's chapter discusses the situation where we overcome the virus infection. In case of coronavirus infection, this is the most common scenario where infections are without symptoms or have mild to moderate symptoms and disease does not progress.

In the previous sections, we have seen infected cells make a protein to boost defenses. They (infected cells) and immune cells also release other chemicals causing a fever. Fever is important to increase metabolism activity of cell and slow virus production. Many other proteins (called interleukins) activate other parts of the immune system. The scout cells (Ch 3), deliver pieces of virus/infected cells to special adaptive immune cells. The CD4 helper cells produce many chemicals needed to fight virus. Some of these increase the killing capacity of innate killer cells. Others direct antibody making cells to start making anti-virus antibodies. Yet another group, powers up the advanced killer cells to end virus containing cells. Killing virus infected cells is similar to a controlled burn to stop a forest fire. By killing cells infected with virus, the virus cannot spread.

Summary of events of a successful elimination of viral infection (connect the numbers with the detail below)

An appropriate response to viral infections (see figure)

1) Early responses can hold off the virus from spreading

2) Interferons produced by cells can boost and get rid of virus and virus infected cells.

3) Innate troops can cause activation of cell damage systems to limit virus spread

4) Scout of innate system pick up dead/dying cells with dead virus parts

5) These scouts deliver the virus parts to adaptive/advanced immune response cells

6) Helper cells coordinate and command the a virus specific response

7) Helper cells boost activation of cell damage systems of innate troops and killers

8) Helper cells tell antibody making cell to start making anti-virus antibodies. Antibodies can block and neutralize virus outside cells.

9) Helper cells boost killing power of killer cells, so they

10) Rid of virus and the virus infected cell.


If everything goes according to plan, the viral infection (be it coronavirus or flu virus), stops. The immune system had done a good job of eliminating the virus. Some parts of immune system save the information as memory cells in case this virus attacks us again.

References:
- Braciale, Thomas J., Jie Sun, and Taeg S. Kim. "Regulating the adaptive immune response to respiratory virus infection." Nature Reviews Immunology 
- Swain, Susan L., K. Kai McKinstry, and Tara M. Strutt. "Expanding roles for CD4+ T cells in immunity to viruses." Nature Reviews Immunology 12.2 (2012): 136-148.2.4 (2012): 295-305.
- Prompetchara, Eakachai, Chutitorn Ketloy, and Tanapat Palaga. "Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic." Asian Pac J Allergy Immunol 38.1 (2020): 1-9.


Next section:
Previous section: Ch 3. Meet your defense forces - immunity to coronaviruses in context of COVID-19

List of all chapters

Sunday, June 14, 2020

Ch 3. Meet your defense forces - immunity to coronaviruses in context of COVID-19

Reading time: 2:07 minutes
Readability: Grade 8


In the previous chapter we saw the consequences of an unchecked viral infection. Before discussing immune function, we need to understand components of the immune system. If we start out by naming the many types of immune cells it can get overwhelming. A function-based approach, lets us appreciate the diversity of immune cells.

There are 2 broad division of the immune response which are further subdivided into other special units (Figure 1)

Figure 1: Function based classification of immune system

1) Innate:

This is an ancient defense system present in all living beings. Plants, fungi, insects, and primitive many-celled organisms have this as the main defense. This early response system is not specific, it can only distinguish what is part of self from enemy. A familiar blood test - WBC count measures the number of white cells in blood, a part of the innate immune system. Its advantage is early response, but it cannot learn and remember past experience.

The cells in this system can be troops or scouts, though each type can do a little of both. Troops have tools to fight and kill infectious organisms. They don’t need extensive training, and develop in large numbers in bone marrow. These properties make them ideal cells to arrive at the scene of an infection early on. A neutrophil is a troop class cell that attacks bacteria that are outside the cell. A “natural killer” cell is troop class, which will kill a virus by killing the cell where virus makes home.

The scouts sample the battlefield to pick up pieces of the dead enemy to identify who has attacked us. This important information is necessary engage special forces of the advanced immune response. Bacteria, virus, fungus, or parasite each need a different advanced immune response. Scouts (antigen presenting cells) are a crucial link between early and advanced response.


2) Adaptive

This immune system engages later in infection. It adapts to the type and strength of infection which is why its called adaptive. A virus causing illness will need different response from bacteria. This system has a cell based response (T cells) to fight infection. The killer cells (CD8 T cells) kill infections (viruses, TB bacterium) that hide inside the cell. 'Helper' cells (CD4 T cells) help, co-ordinate, command the adaptive immune response.

The reason why HIV is so devastating is because the HIV virus eliminates these helpers. By taking out, commanders, HIV causes AIDS and infections that otherwise we can handle.

This system also includes the antibody response. These are proteins produced by B-cells of the adaptive immune system. Antibodies can attack any organisms that are in the blood stream and in tissue but outside of the cells. Antibodies blocks and neutralizes virus before it enters and hides in a cell. Many vaccines work as they designed to induce a strong antibody response.


With coronavirus, we are starting to understand which parts of the immune system engage. The early innate system arrives at site of damage from virus. Killer cells and antibodies play a role. In the later chapters we will see each of these in detail.

Next section: Ch 4. A favorable outcome - immunity to coronaviruses in context of COVID-19
Previous section: Ch 3. Meet your defense forces - immunity to coronaviruses in context of COVID-19
List of all chapters

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