HOW DOES THE IMMUNE SYSTEM RESPOND to the novel coronavirus (SARS-Cov-2)? Where is the problem?

COVID-19 disease is caused by a new type of coronavirus, SARS-CoV-2. Although this virus's genome has been mapped, unknowns remain about its relationship with the immune system. Let us consider in light of current research how our immune system responds to SARS-CoV-2.

Research so far has given us clear information about the stages of novel coronavirus infection. Not everyone exposed to SARS-CoV-2 becomes infected, and not every infected patient develops severe respiratory disease.

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SARS-CoV-2 infections develop in 3 stages:

Stage 1: No symptoms. This is the asymptomatic incubation stage. The virus generally cannot be detected at this stage. People at this stage are "silent carriers." Viral infection can be controlled easily.

Stage 2: Mild-to-moderate symptoms. Symptoms begin to appear, and the virus can be detected. Severe symptoms do not occur at this stage.

Stage 3: Severe symptoms and hospitalization. The person has a very high viral load and develops severe respiratory infections. Around 20% of infected people progress to stage 3 and require hospitalization. The condition becomes life-threatening.

From the perspective of prevention, people in stage 1 play the most important role in spreading the virus. They spread it unknowingly. The first examples of this were seen in countries such as Germany and Italy.

Analyses involving 1000 patients in Wuhan, China, where the outbreak began, found that only about 20% of cases progressed to stage 3. Patients over 65 were also found to be at high risk of progressing to the severe stage.

One of the biggest unanswered questions is why some people develop severe disease while others do not

Frankly, our current knowledge of the immune system cannot clearly explain these differences in disease distribution.

The immune response to SARS-COV-2 infection has two stages:

The figure above explains the immune system's two-stage response to SARS-CoV-2. After incubation, SARS-CoV-2 causes non-severe symptoms and an immune response develops. Successful elimination of infection depends on the patient's health and HLA haplotypes. If the patient's general health is poor, the disease progresses to the severe stage. An inflammatory response then develops, causing substantial lung damage. At this stage, enzymes that synthesize hyaluronic acid (HA) can be blocked, or drugs that eliminate the hyaluronic acid molecule can be used. Mesenchymal stem cell treatment can block inflammation and enable tissue repair.

Note: Increasing immune system activity is important in the first stage of COVID-19. In the second stage, suppressing excessive immune activation and inflammation is vital.

1. During the incubation and non-severe stages, a virus-specific adaptive immune response is needed. Antibody or interferon treatments that activate the immune system may therefore be used in patients at this stage. In other words, if the immune system can develop antibodies against the virus early, that is a good thing; if it cannot, the infection progresses. However, it is important to emphasize that the development of an effective immune system depends on a person's general health and genetic makeup. Genetics influences an individual's immune response to pathogens. If the immune system has an inherited defect, the virus spreads rapidly and damaged tissues increase. This occurs particularly in organs such as the kidneys and intestines with high ACE2 receptor activity, which the virus uses to enter cells. Damaged cells increase inflammation.
2. Lung inflammation in the severe stage causes respiratory disease. Some patients who recover from the novel coronavirus, though currently very rarely, may carry the virus after discharge and even become infected again. This suggests that the immune system has difficulty eliminating the virus completely and that a vaccine will not work in these people. For this reason, people who recover during the initial stages should be monitored through viral testing and T-cell responses. Major histocompatibility complex antigen loci (HLA), which act like cellular identity cards, play an important role in genetic susceptibility to infectious diseases. HLA enables activation of T cells through the binding of viral proteins. Susceptibility to infectious diseases such as tuberculosis, leprosy, HIV, hepatitis B and influenza is associated with certain HLA haplotypes. Different HLA haplotypes are therefore associated with different disease susceptibilities. It appears advantageous for antigen-presenting immune cells that HLA molecules on the surface of normal cells can bind SARS-CoV-2 viral peptides/antigens. Identifying HLA haplotypes is very important for understanding individuals' immune responses.

Thus:

• People's clinical condition can be assessed correctly, and treatment can be planned more accurately.
• SARS-CoV-2 vaccination strategies in the general population can be planned correctly.

Cytokine release syndrome affects patients in the severe stage. This syndrome results in organ damage through excessive activation of the immune system. Treatments blocking cytokines such as IL-1 and TNF can be used against cytokine syndrome. It is important to emphasize that these approaches are still being tested in COVID-19 clinical trials.

Lung damage is one of the most important obstacles to recovery in patients in the severe stage. Mesenchymal stem cells try to repair damaged lung tissue by producing growth factors. Mesenchymal stem cell therapy is still being tested in clinical trials. An excessive immune response to coronavirus causes tissue damage and leads to acute respiratory distress syndrome (ARDS). In this syndrome, lung inflammation develops rapidly and results in death in almost 50% of cases. Symptoms in ARDS patients include short, labored, rapid breathing. Severe patients admitted to intensive care generally require a mechanical ventilator, and those unable to breathe may need extracorporeal membrane oxygenation (ECMO) to support life. Computed tomography (CT) of the lungs has revealed characteristic white patches called "ground-glass" appearances, containing fluid in the lungs. Recent autopsies confirmed that the lungs had turned into a clear, fluid jelly-like consistency, closely resembling wet drowned lungs. Although the nature of this clear jelly appearance has not yet been determined, hyaluronic acid (HA) is associated with ARDS. Levels of inflammatory cytokines, IL-1 and TNF, are high in the lungs of COVID-19 patients. These cytokines increase hyaluronic acid production in CD31 + endothelium, lung alveolar epithelial cells and fibroblasts. Reducing HA levels or inhibiting HA production therefore offers great hope for helping COVID-19 patients breathe.

It is important to emphasize that there is limited research on how coronavirus affects the immune system. The key condition for developing effective vaccines is clearly understanding how the virus affects the immune system.

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