Abstract
Objective: In some individuals, coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leads to a variety of serious inflammatory symptoms, including blood clotting and acute respiratory distress. Death due to COVID-19 shows a steep rise in relation to age. Comorbidities such as type 2 diabetes mellitus (T2DM), hypertension, and cardiovascular disease also increase susceptibility. It has been reported that T-cell regulatory dipeptidyl peptidase 4 (DPP4; cluster of differentiation 26 (CD26)) binds to the external spike (S) glycoprotein of SARS-CoV-2 as a receptor, for the viral entry into the host cell. CD26 is expressed on many cells, including T and natural killer (NK) cells of the immune system, as a membrane-anchored form. A soluble form (sCD26) is also found in the blood plasma and cerebrospinal fluid (CSF).Approach and results: To investigate a possible relationship between sCD26 levels, age and pathology, serum samples were collected from control, T2DM and age-related dementia (ARD) subjects. A significant reduction in serum sCD26 levels was seen in relation to age. ARD and T2DM were also associated with lower levels of sCD26. The analysis of blood smears revealed different cellular morphologies: in controls, CD26 was expressed around the neutrophil membrane, whereas in T2DM, excessive sCD26 was found around the mononucleated cells (MNCs). ARD subjects had abnormal fragmented platelets and haemolysis due to low levels of sCD26.Conclusions: These findings may help to explain the heterogeneity of SARS-CoV-2 infection. High serum sCD26 levels could protect from viral infection by competively inhibiting the virus binding to cellular CD26, whereas low sCD26 levels could increase the risk of infection. If so measuring serum sCD26 level may help to identify individuals at high risk for the COVID-19 infection.
Highlights
A novel coronavirus, severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) is the cause of the latest pandemic, characterised with severe acute respiratory syndrome (ARS) and high mortality due to both a direct cytotoxic viral effect and a severe systemic inflammation [1,2,3]
Our findings suggest that T-cell regulatory cluster of differentiation 26 (CD26) is expressed in different organs from tonsil, spleen, gut mucosa to brain and soluble CD26 (sCD26) may play a crucial role as a decoy receptor which could inhibit the entry of the virus through cell surface, allowing more time for neutralising antibodies to be raised against the SARS-CoV-2 spike protein
We observed a significant reduction in serum sCD26 levels with age and in type 2 diabetes mellitus (T2DM) subjects compared with age-matched controls
Summary
A novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2) is the cause of the latest pandemic, characterised with severe acute respiratory syndrome (ARS) and high mortality due to both a direct cytotoxic viral effect and a severe systemic inflammation [1,2,3]. All coronaviruses (CoVs) utilise a portion of the spike protein called the receptor-binding domain (RBD) to recognise and attach to the surface of human cells, allowing the viral particle to gain entry through the plasma membrane [10,11]. Differential expression of ACE2 and DPP4/CD26 as receptors of spike glycoproteins may help to explain the heterogeneity of clinical features in people infected with different CoVs [15,16]. SARS-CoV-2 S protein requires a protease, such as Furin, Trypsin, human airway trypsin-like protease, cathepsin-L or the transmembrane protease serine 2 (TMPRSS2) [16,17,18,19]. ACE2 or CD26 may be activated by proteolytic cleavage by TMPRSS2 or cathepsin-L in late endosomes in a pH-dependent manner but the virus can be activated by trypsin-like proteases at the cell surface in a pH-independent manner [19,20]
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