Why Our Immune System Cannot Leave the Coronavirus Alone

Cytokine storm or (worse) hurricane is the lesser of two evils.

Upon the invasion of foreign entities, the immune system detects its unusual molecular shape that indicates a potential threat. Better safe than sorry, the immune system eliminates it, despite that it may not do the body any harm. These cases include organs transplantations, autoimmune diseases, or allergies. Similarly, for virus invasion, the immune system is programmed to eradicate it at all costs.

Inflammation in a Nutshell

Inflammation initiates the elimination process. Immune cells ramp up the production of pro-inflammatory cytokines and chemokines. They serve many functions: From activation of other immune cells to vasodilation (allowing more blood flow carrying immune cells) to cell damage (via mechanisms such as reactive oxygen species production, cell membrane disruption, or apoptosis induction) to clearance of cell debris to cell repair.

As inflammation causes cell damage, excessive of it harms nearby healthy cells as well. Excessive inflammation happens when the body is overwhelmed by the foreign antigens or when the immune system failed to regulate itself properly. The latter is often due to a sub-compromised immune system brought about by environmental, genetic, or lifestyle factors.

Consider the first case when a heavy coronavirus load is present — either from initial infection or progressive replication. Cytokine storm happens and causes acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). As coronavirus load and tissue damage increases, cytokine hurricane that causes lethal multi-organ failure occurs.

If inflammation could generate too much collateral damage, why start it in the first place?

* Image by rawpixel.com

If Coronavirus Is Left Alone

The answer lies in the threat the foreign entity could cause. Pathogens — be it viruses, bacteria, fungi, helminth, protozoa, or prions — could wreak havoc in the body if left alone. This article will take SARS-CoV-2 — also applicable to coronaviruses in general — as a model; its life cycle looks like this:

1. The virus spike protein bind to the ACE2 receptor on the epithelial and endothelial cells of the respiratory tract.
2. The ACE-2 binding changes the shape of the spike protein in such a way that it fuses with the cell membrane.
3. After fusion, the TMPRSS2 protein on the cell surface clears the ACE receptor to enable virus entry.
4. Inside the cell, the virus releases its genetic material called RNA that enters the cell nucleus.
5. Inside the nucleus, the virus uses the cell machinery to transcribe its RNA into proteins, which are then assembled into a virion.
6. Newly produced virions approach the cell membrane where they acquire an envelope to become a mature virus that can infect other cells.
7. Back to phase 1.

The last step where coronaviruses obtain their envelope consumes resources from the host cell membrane. This process, if repeated enough times, ruptures the cell membrane. And inflammation also aggravates the membrane lysis. As per how researchers at the Center for Drug Evaluation and Research in the United States describe Covid-19: “Epithelial and endothelial cells with actively replicating virus will eventually become apoptotic and die, further contributing to tissue inflammation.”

* Source: Lebeau, G. et al. Deciphering SARS-CoV-2 Virologic and Immunologic Features. Int. J. Mol. Sci. 2020, 21, 5932. https://doi.org/10.3390/ijms21165932.

The Lesser of Two Evils

The last step where coronaviruses rob parts of the cell membrane to form its envelope also alters the chemical properties of the cell membrane — making it detectable by immune cells. The immune system now aims to kill the infected cell as quickly as possible to prevent further virus replication and spread.

The degree of inflammation depends on how much the virus has replicated and spread. Inflammation would be mild — a cytokine drizzle — if the immune system handles the virus invasion early. Otherwise, more severe inflammation called the cytokine storm or, worse, cytokine hurricane would occur. In this way, the cytokine drizzle, storm, and hurricane represent the three phases of Covid-19 severity.

At least the cytokine storm or hurricane is the lesser of two evils. It gives the immune system a chance to deal with coronaviruses that are rampaging cell membranes. Might as well die trying, the immune system must’ve thought.

This article was originally published in Microbial Instincts with minor modifications.

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