A primary defense against SARS-CoV-2: defensins

This article is an extension of a previous series which is now available in anthology form in the book, “Natural immunity and Covid-19: what it is and how it could save your life”. Here we present the first part of a small series on defensins, small molecules that protect us against infectious diseases.

One of the most important layers of our body’s defense against SARS-CoV-2 is our innate immune system. The innate immune system protects our body from germs, viruses, bacteria and parasites that we have never encountered before. While much of the public attention and awareness of human immunity focuses on adaptive or acquired immunity, innate or natural immunity explains why most people infected with SARS-CoV- 2 have few, if any, serious symptoms.

Now, a family of molecules called defensins is the latest to be involved in our natural defense against SARS-CoV-2.

Presentation of defensins

Defensins are an ancient family of proteins that stretch far back in our evolutionary history and are active in most multicellular organisms. In humans, they are found throughout the body and are classified as either alpha defensins or beta defensins based on their structure. Alpha defensins are further classified as human neutrophil peptides (HNPs) or human defensins (HD). There are four forms of human neutrophil peptides (HNP 1-4) and 2 forms of human defensins (HD 5-6). HNP 1-4 are produced by neutrophils in the circulatory system, while HD 5-6 are produced by Paneth cells. Paneth cells are specialized epithelial cells that line the surface of the small intestine.

Many beta-defensin genes have also been discovered in the human genome, however, only three have been functionally classified. These are human beta-defensins 1-3 (HBD 1-3) and they are produced by the epithelial cells of several organs.

Defensins are considered antimicrobial peptides and are known to defend against bacteria, fungi, and viruses. While some defensins kill invading microbes directly, others are able to recognize infected cells and kill them before the infection spreads to healthy cells.

Now, recent research has shown that certain defensins may play a role in suppressing SARS-CoV-2 infection.

How do defensins work?

Defensins ward off microbial infections through a wide variety of mechanisms. However, the most frequently cited mechanism is membrane rupture. Defensins can kill cells by inserting themselves into the cell membrane to create holes in the membrane. This causes cell contents to leak out, leading to cell death.

One of the most powerful characteristics of defensins is that they have a Janus face – one side of them is positively charged while the other side is negatively charged. This makes them amphipathic molecules and allows them to interact favorably with charges on any membrane to cause membrane disruption and cell death.

The question that remains is: do defensins have a similar effect on SARS-CoV-2? Recent research suggests yes.

Defensins inhibit SARS-CoV-2 infection

To investigate this question, Chuan et al. started by inducing the SARS-CoV-2 spike protein on fluorescent cells.

To test whether defensins could inhibit infection, Chuan et al. treated fluorescent spike protein cells with defensins for 1 hour. They then introduced the spike protein cells into cells with ACE2 receptors. Typically, when SARS-CoV-2 infects a cell, its spike protein binds to ACE2 receptors to enter a cell and transfer its viral RNA. The researchers were able to measure the number of infected ACE2 cells, based on the transfer of fluorescent material.

Surprisingly, they found that four alpha defensins exhibited significant anti-SARS-CoV-2 activity. These were: HNP-1, HNP-2, HNP-3 and HD5. HNPs 1-3 suppressed infection by 50% while HD5 suppressed infection by 60%. All four defensins were effective at physiological concentrations of each molecule. HD6 also blocked SARS-CoV-2 infection, but only at a much higher concentration that was outside the physiological range, indicating that it might not be as effective against SARS-CoV- 2 in the body.

When this experiment was repeated with spike proteins from the Alpha and Gamma variants of SARS-CoV-2, the researchers found that the defensins were less effective at suppressing the infection, suggesting that these variants were more resistant to the defensins. .

Defensins inhibit viral entry

Then, Chuan et al. sought to infer whether defensins suppress SARS-CoV-2 infection by preventing the virus from entering the cell or by inhibiting the ability of the virus to replicate. To do this, the researchers first exposed the ACE2 cells to the spike protein cells, allowing the virus to enter the ACE2 cells. They then treated the already exposed ACE2 cells with defensins. After incubating the cells for three days, the researchers found that the defensins showed no anti-SARS-CoV-2 effect, suggesting that the defensins block SARS-CoV-2 infection by preventing the virus from enter the cell first.

So how do defensins prevent SARS-CoV-2 from entering the cell? A separate study by Wang et al. at Army Medical University in Chongqing, China, might have the answer.

Wang et al., used computer modeling techniques to determine how HD5 alpha defensin interacts with SARS-CoV-2 and ACE2 receptors. Through computer simulations, they found that HD5 has a higher binding affinity for ACE2 receptors than for SARS-CoV-2 proteins. This indicates that HD5 may prevent SARS-CoV-2 from infecting cells by blocking ACE2 receptors and “masking” healthy cells from the virus.

This study marks a significant advance in our understanding of how innate immunity protects us against SARS-CoV-2. As we continue to dig deeper into how defensins prevent SARS-CoV-2 infections, we may uncover new avenues for drugs and treatments.

Intestinal defensins

One of the abnormalities of SARS-CoV-2 infection is that the lining of the intestine is much richer in ACE2 than the lungs, but the main symptoms of SARS-CoV-2 infection are respiratory. Some have speculated that it is the effectiveness of the innate immune defense in the gut that enables the gut to resist the effects of SARS-CoV-2.

One of the main defensins identified in Chuan et al. and Wang et al. is HD5. HD5 is very abundant in the intestine and its production is triggered by the release of cytokines.

In an article published by researchers from the Institut Pasteur, scientists have made an interesting discovery. They found that invading microbes in the gut can activate a molecule called interleukin-3. When interleukin-3 is activated, it produces pro-inflammatory cytokines which trigger the production of HD5.

The gut already contains multiple defenses against viral infection. Its mucous membrane surface makes it more difficult for the virus to attach to ACE2 receptors. The adaptive immune system also provides a high level of protection by producing the antibody immunoglobulin A (IgA) which is transmitted across the surface of intestinal epithelial cells to prevent infection.

Now, these studies indicate that the gut contains a vigorous innate immune system that responds to SARS-CoV-2 by activating interleukin-3 and triggering the production of HD5. Since HD5 has antiviral effects and can kill infected cells, this innate immune response may explain why the gut appears to be especially protected against the effects of SARS-CoV-2.

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