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dcyphr | Mechanism of inflammatory response in associated comorbidities in COVID-19

Abstract

Individuals with underlying medical conditions display a worse outcome after SARS-CoV-2 infection. This study looks at several underlying medical conditions and its effect on COVID-19 infections. Studies show that obese individuals are more likely to develop infections. The fat tissue serves as a viral reservoir, which makes it harder to control the infection. infection. Diabetic individuals show a higher rate of inflammatory conditions. Hypertensive individuals are treated with drugs to reduce blood pressure. These drugs often work through ACE2 and ARB receptors and are often inhibitors of ACE2 and ARB receptors. Use of these drugs can lead to increased production of ACE2 which is what SARS-CoV-2 uses for entry into the cell. People with obesity, diabetes, or hypertension have an uncontrolled release of pro-inflammatory cytokines. Cytokines are a small and broad class of proteins involved with cellular signaling. This can lead to what is known as the cytokine-storm phenomenon. As there are no currently approved SARS-CoV-2 antiviral therapy, efforts should be placed upon controlling the inflammatory response.


Introduction

Diabetes, hypertension, and other cardiovascular disease (CVD) are strongly related to higher risks of mortality and severity with COVID-19 infection. The fat cells in obese patients increased pro-inflammatory cytokines and proteins. This can generate chronic alterations in body chemistry. It is thought that SARS-CoV-2, SARS-CoV, and MERS-CoV suppress antiviral IFN-gamma immune responses. In the late stages of infection this suppression causes a rapid increase in white blood cells. Neutrophils and monocytes/macrophages flood the body and release pro-inflammatory cytokines that can damage lung tissue.

According to genome sequencing, the human SARS-CoV-2 is 89% identical to bat SARS-like-CoVVZXC21. Analysis of all coronaviruses shows that bats acted as the primary transmission route of SARS-CoV-2 to humans. SARS-CoV-2 enters the cell in a similar way to SARS-CoV. Therefore, it is suggested that both use ACE2 receptors found in the lung tissue to gain entry to the cell.


Methods

The researchers searched databases such as PubMed up until April 23, 2020 using strategic keywords. The results were then cross referenced.


Results

( 1 ) Metabolic Disease

Around 25% of adults 40-49 years old have metabolic syndrome (MS). This percentage increases to 40% at age 60. When present, metabolic syndromes double the mortality of patients with diabetes. Metabolic syndromes also triple the mortality of those with cardiovascular diseases (CVD). Metabolic Syndrome can be controlled with action through the renin-angiotensin-aldosterone system (RAAS), which is a hormone system involved with blood pressure regulation.


( 2 ) Obesity

Obesity causes inflammation which results in metabolic changes that can cause other comorbidities. The over production of inflammatory adipokines (cytokines in fat tissue) from gut fat can affect the immune response, impair movement of white blood cells, and change the specificity of macrophages. This will prevent the right type of white blood cell from being produced, and prevent its movement to the proper site of infection. This can help to explain the cytokine storm that we observe in severely infected COVID-19 patients. This chronic inflammation is a result of insulin resistance. The increase in oxidative stress on the fat participates in the misregulation of the pro-inflammatory cytokines. This can produce metabolic syndrome.


( 3 ) Diabetes mellitus

Diabetes mellitus (DM) is a major risk factor for severity and mortality for individuals infected with SARS-CoV-2. Studies have shown that diabetes mellitus is associated with increased inflammation of the lungs. The risk of diabetics cannot be eliminated. It can be reduced by controlling blood sugar. Diabetes was seen as an important risk factor in pandemic influenza (H1N1) in 2009, SARS-CoV, and MERS-SCoV. The human immune system used sugar polymers in a variety of host-pathogen and host-host interactions. The receptor that recognizes these sugars for the immune system is known as a C type lectin receptor (CLRs). These C type lectin receptors can also be activated via excessive blood sugar, which will lead to an uncontrolled pro-inflammatory immune response. Excessive glucose concentrations in the body could lead to possible changes in the way Spike protein of the virus binds to human cells. This could lead to changes in immune response and intensity of infection.


( 4 ) Hypertension

Angiotensin converting enzyme (ACE2) is what SARS-CoV-2 uses to gain entry to the cell. ACE2 belongs to a class of receptors known as ACE receptors. ACEi are inhibitors of ACE receptors, including ACE2. ACE receptors are a part of the Renin Angiotensin System which is a system made to help regulate blood pressure. When ACE inhibitors are used, it causes increased production of the ACE2 protein. This could be a risk factor as this could give SARS-CoV-2 more chances to gain cellular entry. However, a study has shown that patients using ACE inhibitors had a reduced inflammation response when infected with SARS-CoV-2. Thus, the group of patients using these ACE inhibitors had better clinical outcomes due to decreased inflammation. There is currently no evidence that ACE inhibitors cause increased production of ACE2 proteins.


( 5 ) Cytokine storm

Patients with severe COVID-19 infections often have what is known as the cytokine storm (CS) phenomenon. This is an uncontrolled release of pro-inflammatory cytokines. This cytokine storm can be triggered by infectious diseases. The cytokine storm can result in systemic inflammation, multiple organ failure, vascular leakage, alveolar edema, and impaired T-cell response. A review of studies shows that more severe patients with COVID-19 have higher levels of pro-inflammatory cytokines. When researchers used antibodies that would bind to these pro-inflammatory cytokines the patients had better clinical outcomes.


( 6 ) Vitamin D and immune response

Vitamin D stands out as a potential immune system regulator. It becomes activated inside the body and turns into activated vitamin D (VD3) which can bind to its receptor VDR. The VDR receptor is produced in immune cells. When activated VDR can alter the production of other genes such as angiotensin converting enzyme (ACE) and VDR. According to a study reviewed by the researchers individuals with critical respiratory infections had reduced levels of VD3. When VD3 was given to these patients they observed a reduction of pro-inflammatory cytokines which resulted in better clinical outcomes. Vitamin D also plays an important role in the regulation of many metabolic pathways. It is vital for regulation of insulin and regulating blood pressure by regulating the ACE receptor production.


Conclusion

Individuals with cardiac or metabolic diseases are more susceptible to SARS-CoV-2 infection. The dysregulation of inflammation leads to a cytokine storm which causes damage to healthy cells. The role of medications used by those with diabetes, hypertension, or other cardiovascular diseases is debatable since they often lead to increased ACE2 expression. This receptor is associated with SARS-CoV-2 entry into the cell and thus increases the risk of infection. To lessen the immune systems dysregulation active vitamin D (VD3) shows promise as a regulator. It has shown that active vitamin D (VD3) can lessen the immune response and reduce associated complications.