An ancient form of immunity protects many against Covid-19 today
An ancient form of immunity protects many against Covid-19 today

An ancient form of immunity protects many against Covid-19 today

One of the most striking features of the SARS-CoV-2 pandemic is that across all variants, most people who are infected have few, if any, severe symptoms. Most people experience mild cold-like symptoms, while the most severe symptoms are limited to only about 10% of those infected. These numbers are even better for those who have been vaccinated. What is the reason why unvaccinated people for the most part appear to be resistant to a virus that has the potential to kill?

The answer lies in our innate immune response.

This series of articles is an extension of an earlier series, which is now available as an anthology in the book, Natural Immunity and Covid-19: What it is and how it could save your life. Here we expand that series based on new research on yet another aspect of the natural (innate) immune system.

The basic feature of the innate immune system is that it protects our body from microbes, viruses, bacteria and parasites that we have not encountered before. Much of the awareness and public awareness of human immunity is focused on adaptive or learned immunity. Learned immunity develops in our bodies after exposure to previous infection or vaccinations. Only in recent years has enormous progress been made in what is perhaps our most important defense system of all: innate immunity.

This story focuses on an unknown aspect of innate immunity and describes a category of proteins called lectins. Lectins are thought to have evolved before antibodies and continue to persist in ours immune system today. It has now been discovered that these lectins can provide two aspects of protection by preventing infection and by limiting the ability of SARS-CoV-2 to replicate and spread.

Introduction to the Lectin family

Lectins are ubiquitous in nature and are considered as pattern recognition molecules. This is because lectins have a special ability to recognize foreign molecules in the body and can activate a reaction to these molecules. The lectin system has many components, including mannose-binding lectin, collectins, and three different ficolines, all of which are pattern recognition molecules that can recognize different molecules and activate different responses. Now, at least two lectins from the lectin family have been implicated in our body’s defenses against SARS-CoV-2: mannose-binding lectin and its related enzyme, MASP-2.

How mannose-binding lectin recognizes SARS-CoV-2 infection

How does mannose-binding lectin recognize foreign molecules in the body? Most invasive microorganisms, cells and viruses contain a surface coated with complex glycan structures or “sugar” molecules. These structures help the microorganism to move, help with aggregation and can serve as a shield to hide the microbe from a host’s antibodies. SARS-CoV-2 is no exception. One of the prominent features of the SARS-CoV-2 virus is its spike (S) protein. Like other microbial proteins, the nail protein is covered with its own unique glycan residues (Figure 2).

Mannose-binding lectin contains several receptors that are used to identify the glycan residues of invading microorganisms. It also contains a stem that activates a defense mechanism called the lectin complement system (Figure 3). Mannose-binding lectin and the lectin-complement pathway developed well before antibodies and are often considered to be proto-antibodies. They are known to play a vital role in defending our body against viruses and bacteria such as HIV, salmonella and streptococci.

The lectin complement cascade and the role of MASP-2

When mannose-binding lectin recognizes an invading pathogen, it initiates the lectin complement cascade by activating MASP-2 and its counterpart, MASP-1. When MASP-2 and MASP-1 are activated, the other two proteins cleave: C2 and C4. The C2 and C4 protein fragments then bind together to form C3 and C5. C3 and C5 can directly kill pathogens by binding together to form holes in the pathogen membrane (lysis). The cleavage of C2 and C4 also releases inflammatory cytokines, which warn other immune cells to help with the attack of the pathogen (Figure 4).

MASP-2 is a crucial enzyme in the lectin pathway. Only MASP-2 can split both C4 and C2. When MASP-2 is inhibited in the body, the lectin pathway can no longer be activated and can no longer defend the body against invading pathogens.

Previous studies have found that activation of the lectin complement system was associated with the development of respiratory distress and failure during viral pneumonia – a prominent symptom of severe SARS-CoV-2 infections. In addition, autopsies of patients infected with SARS-CoV-2 have shown evidence of lectin complement activation through the presence of C5, C3, C4, and MASP-2 proteins.

The question is, are mannose-binding lectin and the MASP-2 proteins responsible for defending our bodies against SARS-CoV-2 through the lectin complement system?

Mannose-binding lectin prevents SARS-CoV-2 infection

In the first leafStravalaci et al. began by determining whether any lectins could bind to SARS-CoV-2. By testing the interactions between specific proteins found in SARS-CoV-2 and each lectin, the researchers found that of the lectins tested, only mannose-binding lectin was consistently bound to the SARS-CoV-2 peak protein.

While this confirmed that the mannose-binding lectin would interact with the peak protein, the researchers had to be sure that mannose-binding lectin would still bind to the peak protein when expressed on the SARS-CoV-2 cell membrane. With this in mind, Stravalaci et al. induced the SARS-CoV-2 peak protein on other cell membranes and found that the mannose-binding lectin continued to bind to the peak protein in its natural conformation (Figure 1).

When mannose-binding lectin interacted with the spike protein, it induced the lectin-complement pathway. Researchers incubated the tip protein in a serum containing mannose-binding lectin as well as other proteins involved in the lectin complement pathway. After running the experiment, the data were clear: the lectin complement was fully activated. Mannose-binding lectin could effectively defend against SARS-CoV-2 infections.

Stravalaci et al. then tested mannose-binding lectin against four variants: Gamma, Alpha, Beta and Delta. Using the same procedures, they found that the mannose-binding lectin was as effective against SARS-CoV-2 variants as it was against the original strain.

Mannose-binding lectin and MASP-2 prevent the spread of SARS-CoV-2

Stravalaci et al. found that mannose-binding lectin could bind to SARS-CoV-2 through its nail protein. However, in a second related history published in Frontiers Immunology, researchers found that lectins may actually have two modes of attack against SARS-CoV-2.

The second study focused on the interactions between mannose-binding lectin and MASP-2 protein with SARS-CoV-2. To test these interactions, Youssif et al. first placed mannose-binding lectin in a serum of SARS-CoV-2 proteins and incubated the cells for one hour. Using this experimental method, they found that, unlike the first paper, mannose-binding lectin showed strong interactions with both the SARS-CoV-2 peak protein and its nucleocapsid protein.

The researchers then tested whether mannose-binding lectin could still interact with the nail protein when expressed on the cell membrane. After inducing the tip protein on other cell membranes and testing their interactions with the mannose-binding lectin, the results confirmed Stravalaci’s results. The mannose-binding lectin continued to bind to the tip protein when expressed on the cell membrane. In addition, they found that this experiment led to the deposition of C3 on the cell membrane, indicating that the lectin complement had been activated.

Youssif et al. then investigated whether MASP-2 could interact with the SARS-CoV-2 tip and the nucleocapsid proteins. After incubating MASP-2 with both proteins, researchers surprisingly found that MASP-2 bound directly to the nucleocapsid protein. When MASP-2 was then incubated with C4, the resulting C4 fragments showed that MASP-2 also retained its ability to cleave the C4 protein. This indicated that not only could MASP-2 be activated by the SARS-CoV-2 nucleocapsid protein, but MASP-2 continued to promote subsequent steps in the complement cascade after binding with SARS-CoV-2.

The nucleocapsid protein is the most abundant and immunogenic protein in SARS-CoV-2. It is a critical component of the virus’ ability to replicate and spread. Recent studies has shown that the nucleocapsid protein also plays a major role in suppressing our innate defenses against SARS-CoV-2. By direct binding to the nucleocapsid protein, this study indicates that mannose-binding lectin and MASP-2 could serve as effective defenses against one of the most dangerous attacks of SARS-CoV-2.

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