Reduction of soluble dipeptidyl peptidase 4 levels in plasma of patients infected with Middle East respiratory syndrome coronavirus

Abstract

Dipeptidyl peptidase 4 (DPP4) is a receptor for MERS-CoV. The soluble form of DPP4 (sDPP4) circulates systematically and can competitively inhibit MERS-CoV entry into host cells. Here, we measured the concentration of sDPP4 in the plasma and sputa of 14 MERS-CoV-infected patients of various degrees of disease severity. The concentration of sDPP4 in the plasma of MERS patients (474.76 ± 108.06 ng/ml) was significantly lower than those of healthy controls (703.42 ± 169.96 ng/ml), but there were no significant differences among the patient groups. Interestingly, plasma levels of IL-10 and EGF were negatively and positively correlated with sDPP4 concentrations, respectively. The sDPP4 levels in sputa were less than 300 ng/ml. Viral infection was inhibited by 50% in the presence of more than 8000 ng/ml of sDPP4. Therefore, sDPP4 levels in the plasma of MERS patients are significantly reduced below the threshold needed to exert an antiviral effect against MERS-CoV infection.

Circulating levels of soluble Dipeptidylpeptidase-4 are reduced in human subjects hospitalized for severe COVID-19 infections

“…Of interest, for the MERS-CoV corona-like virus it was explicitly shown that CD26 is the important membrane bound protein mediating internalization of the virus into host immune cells. Treatment with sDPP-4 has been proven to block the entry of corona like viruses into host cells via competitive inhibition in vitro and lower serum levels of sDPP-4 have been found in MERS-CoV infected human subjects compared to healthy controls in vivo [6].…”

“…Given the small sample size we used a case control design for the statistical analysis by recruiting age, sex and BMI matched controls from our cross-sectional FoCus cohort comprising almost 2000 human individuals [14]. Of interest, as it was found for MERS-CoV corona-like virus infections [6], we identified a significant decrease in circulating sDPP-4 in the serum of COVID-19 patients compared to controls (p = 0.02) [ Fig. 1].…”

Elevated Human Dipeptidyl Peptidase 4 Expression Reduces the Susceptibility of hDPP4 Transgenic Mice to Middle East Respiratory Syndrome Coronavirus Infection and Disease

“…While the levels of sDPP4 vary significantly, even among healthy individuals, it has been shown that the intensities of sDPP4 expression in the circulation, along with its intrinsic enzymatic activity, could be a factor in dictating the severity of many human diseases, including malignancies, autoimmune and inflammatory diseases, diabetes mellitus and other metabolic syndromes, and chronic infectious disease such as AIDS and hepatitis C [ 4 , 10 , 11 , 14 , 15 ]. It has been recently reported that serum levels of sDPP4 expression in confirmed MERS patients were significantly reduced when compared to those of healthy individuals [ 16 ]; however, the suggestion that these reduced levels could serve as biomarkers for susceptibility requires knowledge regarding the levels in MERS cases before onset of infection and disease. In addition, further studies of the therapeutic value of shDPP4 as either a significant resistance factor or a potential countermeasure for MERS-CoV in humans is warranted.…”

Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

“…Increased risk of nasopharyngitis and urinary tract infection but no association of upper respiratory tract infections in T2DM patients (Amori et al, 2007;Gamble et al, 2018) Potential adverse effect on MERS patients (Inn et al, 2018;Raj et al, 2013) Potential therapeutic effect on HCV patients (Decalf et al, 2016;Riva et al, 2014) No effect on HIV patients (Dube et al, 2019;Goodwin et al, 2013)…”

“…Inn and colleagues observed that sDPP4 in the plasma of MERS patients is significantly lower than those of normal volunteers. The levels of immune-suppressive cytokine IL-10 and protective growth factor epidermal growth factor (EGF) are significantly negatively and positively correlated with plasma sDPP4 concentration, respectively (Inn et al, 2018). Thus, it is assumed that exogenous sDPP4 may have therapeutic potential in MERS patients and that application of gliptins in MERS patients may adversely affect the pathological and immune processes of this disease.…”