ABSTRACT
The coronavirus disease is caused by the novel beta coronavirus, SARS COV2 (Severe Acute Respiratory Syndrome Coronavirus 2) is presently one of the leading cause of mortality rate. This virus penetrates the human body via the ACE2 receptor. Recent evidence suggests a new receptor, the DPP4/CD26 receptor via which the SAR COV2 enters the body. DPP4 oringinally known as the T-cell antigen CD26 has gained a key role in the management of Type 2diabetes mellitus, the protein regulates glucose homeostasis and inflammation via enzymatic activity and non-enzymatic immunomodulatory effects. DPP4 (Dipeptidyl Peptidase 4) is expressed on epithelia and endothelium. In humans, DPP4 is strongly expressed on the apical surfaces of polarised epithelium including lung, liver, pancreas (acinar cells),intestine and kidney tubules. DPP4 is also present on the inner surface of capillary endothelial cells, it is involved in several physiological and pathological processes like inflammation, enzymatic degradation and immunological responses in the body. This literature discusses the role of DPP4 in Covid19 type 2 diabetes patients, the factors influencing the increase in the expression of DPP4 receptors and the potential role it plays in Covid19 infected individuals with type 2 diabetes. It also sheds light on the basis that Dpp4 inhibitors may play a role in the management of Covid19, although there are other contradicting research surrounding this hypothesis, studies are currently being carried out to fully understand the relationship between SARS COV2 and Dpp4 and the mechanism of action of Dpp4 inhibitors for the management of Covid19.
CHAPTER ONE
1.0 INTRODUCTION
The recently emerged contagious disease is currently a leading pandemic worldwide, ranking third on the list of causes of mortality (WHO, 2020). COVID-19 (Coronavirus Disease 2019) is a disease caused by the novel severe acute respiratory syndrome, coronavirus disease. This disease belongs to the same family as the SARS COV that appeared in 2002 and the MERS (Middle East Respiratory Syndrome) that showed up in 2012 in the middle east (Sorlerte et al., 2020). It was first recognised in a small village, Wuhan China and has spread to various countries across the world.
Currently this viral disease has affected over a hundred million people with more than three million deaths and counting. Symptoms associated the disease include pneumonia, cough, fever, difficulty in breathing and lung infection caused by inflammation (Adhikari et al., 2020). According to WHO in July 2020, this disease is transmitted via contact, air droplets blood, air, fecal –oral, mother to child and animal to humans, transmission can occur directly, indirectly or close contact with infected individuals.
The figure (fig 1) below shows a chart representation of the number of deaths caused by different diseases.
FIG 1
CHART REPRESENTATION OF THE LEADING CAUSES OF DEATH GLOBALLY (WHO 2020)
This infectious disease is aggravated by various factors such as hypertension, obesity, diabetes mellitus, metabolic disorder, gender and aging, thus increasing the incidence of severity and mortality (Bassendine et al., 2020, Rashedi et al., 2020). Our main focus is on diabetes mellitus mainly the type 2 diabetes mellitus and its contribution to the severity and mortality of covid19 via DPP4 enzyme.
Fig 2 RISK FACTORS FOR SEVERITY AND MORTALITY OF COVID 19 (WHO 2020).
Considering that diabetes mellitus is one of the most important comorbidities in SARS COV2 patients. It is necessary to classify all the aspect concerning all the links between the two conditions to offer scientific and clinical knowledge to tackle the pandemic in the best way.
CHAPTER TWO
TYPE 2 DIABETES MELLITUS
Diabetic mellitus according to the World Health Organization is a chronic metabolic disease condition caused by elevated levels of blood glucose (blood sugar), glycosuria and negative nitrogen balance, which leads over time to serious damage to the heart, blood vessels, kidney, eyes, and nerves.
Diabetes mellitus is classified into the type 1 diabetes mellitus and the type 2 diabetes mellitus. The most common is type 2 diabetes mellitus (Non-insulin dependent diabetes mellitus), which is caused by either abnormality of the gluco-receptors of the Beta cells on the islets of the pancreas that results to decreased secretion of insulin from the pancreas or reduced sensitivity of peripheral tissues to insulin as a result of down regulation of insulin receptors such that the tissues lacks sufficient insulin for the degradation of glucose.
Drug therapy for type 2 diabetes mellitus include sulfonylureas, biaguanides, Dipeptidyl peptidase inhibitors, Thiazolindinediones, Meglitinide analogues, Alpha glucoside inhibitors.
In type 2 diabetes mellitus, there is an increase in expression of certain enzymes , DPP4 (dipeptidyl peptidase 4) being one of them (Rohrborn et al., 2015).
Type two diabetes is one of the major risk factors amongst other fore mentioned risk factors for severity and mortality of covid19 (Scheen et al., 2020).
CHAPTER THREE
DPP4 (DIPEPTIDYL PEPTIDASE ENZYME).
Fig 3: Quaternary Structure of the dpp4 enzyme.
3.1 DPP4 (Dipeptidyl peptidase)
DPP-4, originally known as ‘T-cell antigen CD26 (cluster of differentiation 26) is a type II trans membrane glycoprotein (Matteucci and Ottavio 2009). It is also a multifunctional soluble and cell-bound serine protease that is abundantly expressed in lymphocytes and adipocytes as well as many other cellular types, including endothelial and epithelial cells. (Drucker 2006). It is also expressed on the gut, liver, pancreas, lungs, kidneys, capillaries. Dpp4 exists in two forms, the soluble form and the membrane bound form (Ahmed et al., 2017). It is involved in many biological and functional processes such as enzymatic, inflammatory and immunological responses ( Christian et al., 2016). Enzymatically, It serves as a regulatory enzyme for cytokines, chemokines and neuropeptides involved in inflammatory, immunity and vascular function (Santana et al., 2015). It is involved in the degradation of the gastric peptides GLP-1 (Glucagon like peptide-1) and the GIP (Gastric Inhibitory Peptide). This peptides are released in the gut and they are involved in the stimulation of the release of insulin from the beta cells of the pancreas (Yoshiki et al., 2015). The regulation of release of insulin plays a role in the level of glucose present in blood. Inhibition of degradation of the gastric peptides controlled by DDP4 increases secretion from the pancreas and enhances postprandial metabolism to treat hyperglycaemia (Trzaskalski et al., 2020). Soluble Dpp4 also plays a role in controlling the progress of inflammation via production of pro inflammatory cytokines(Trzaskalski et al., 2020). DPP4 increases the expression and proliferation of T-lymphocytes by binding to adenosine and via its degradation (Bessendine et al., 2020). Adenosine deaminase is a potent suppressor of T-cell proliferation and activation and inducing it degradation will increase T-cell proliferation. It stimulates NK and B cells proliferation by cleavage of Neuropeptide Y. (Bessendine et al., 2020). This plays a substantial role in immune system regulation.
3.2 TYPE 2 DIABETES MELLITUS AND DPP4 ENZYME.
DPP4 is dysregulated in type 2 diabetes mellitus (Solerte et al., 2020). DPP4 contributes to the pathogenesis of diabetes mellitus, via cleavage of the insulinotropic hormones in the gut, GLP-1 and GIP (Santana et al., 2015, Bessenadine et al., 2020). There is an increased in expression and activity of dpp4 in the diabetic patients and several other disease like obesity, cancer, inflammation (Rohrborn et al., 2015). An increase in the activity of DPP4 contributes to hyperglycaemia, because of an increase in the breakdown of gastric peptides/hormones necessary for the release of insulin ( Stoian et al., 2020). It also results in chronic inflammation (Rohrbon et al., 2015). These activities will further lead to distorted immune responses and inflammation.
CHAPTER FOUR
MECHANISM OF ENTRY OF SARS COV 2
To fully understand the role of DPP4 in viral entry, it is paramount to understand the conventional mechanism of entry of SARS COV2 into the human body.
The mechanism of entry of corona virus was controversial in 2004. In 2008, Wang and colleagues established the endocytic pathway as an alternative entry pathway apart from direct fusion with the plasma membrane based on their observations of SARS-CoV.1 (Gil et al., 2020).
The SARS COV2 is a single, positive strand RNA virus that causes severe respiratory syndrome in humans (Yesudhas et al., 2021). The mechanism of entry of SARS COV2 is a via the virus spike protein (Jain et al., 2020, Zhang et al., 2020). The spike protein binds to the human ACE receptor (ACE2) via its receptor binding domain. The SARS COV2 entry needs several activating proteases like cell surface protease, TMPRSS2 and lysosomal proteases (Jain et al., 2020), they activate the spike membrane fusion. A research also shows that the virus uses the sugar receptors in the human cells to gain entry, because it has a high affinity for it (Yesudhas et al., 2021). The SARS COV2 has a high binding affinity for the human ACE2 and the Receptor binding domain (RBD).