Glycation-Driven Inflammation: COVID-19 Severity in Pregnant Women and Perinatal Outcomes

Abstract

The link between being pregnant and overweight or obese and the infectivity and virulence of the SARS CoV-2 virus is likely to be caused by SARS-CoV-2 spike protein glycosylation, which may work as a glycan shield. Methylglyoxal (MGO), an important advanced glycation end-product (AGE), and glycated albumin (GA) are the results of poor subclinical glucose metabolism and are indices of oxidative stress. Forty-one consecutive cases of SARS-CoV-2-positive pregnant patients comprising 25% pre-pregnancy overweight women and 25% obese women were recruited. The aim of our study was to compare the blood levels of MGO and GA in pregnant women with asymptomatic and symptomatic SARS-CoV-2 infection with pregnant women without SARS-CoV-2 infection with low risk and uneventful pregnancies and to evaluate the relative perinatal outcomes. The MGO and GA values of the SARS-CoV-2 cases were statistically significantly higher than those of the negative control subjects. In addition, the SARS-CoV-2-positive pregnant patients who suffered of moderate to severe COVID-19 syndrome had higher values of GA than those infected and presenting with mild symptoms or those with asymptomatic infection. Premature delivery and infants of a small size for their gestational age were overrepresented in this cohort, even in mild-asymptomatic patients for whom delivery was not indicated by the COVID-19 syndrome. Moreover, ethnic minorities were overrepresented among the severe cases. The AGE–RAGE oxidative stress axis on the placenta and multiple organs caused by MGO and GA levels, associated with the biological mechanisms of the glycation of the SARS-CoV-2 spike protein, could help to explain the infectivity and virulence of this virus in pregnant patients affected by being overweight or obese or having gestational diabetes, and the increased risk of premature delivery and/or low newborn weight.

COVID-19, Pregnancy, and Diabetes Mellitus

“…Even with subclinically elevated blood glucose levels, which are indicative of oxidative stress, there is an increased structural glycation of the SARS-CoV-2 spike protein, which was demonstrated by increased levels for methylglyoxal and glycated albumin [13]. The virus uses its glycosylated trimeric spike proteins to bind to the ACE2 receptor [14].…”

Adverse perinatal outcomes in gestational diabetes mellitus with and without SARS-CoV-2 infection during pregnancy: results from two nationwide registries in Germany

“…Uptake of SARS-CoV-2 occurs through its binding to the ACE2 receptor,6 which is more expressed by hyperinsulinemia 7. Even with subclinically elevated blood glucose concentrations, there is an increased structural glycation of the SARS-CoV-2 spike protein, facilitating its binding to the ACE2 receptor 8 9. From the upper respiratory tract, virus distribution is followed by systemic inflammation and entry into target organs, such as the endocrine pancreas 10.…”

“… 7 Even with subclinically elevated blood glucose concentrations, there is an increased structural glycation of the SARS-CoV-2 spike protein, facilitating its binding to the ACE2 receptor. 8 9 From the upper respiratory tract, virus distribution is followed by systemic inflammation and entry into target organs, such as the endocrine pancreas. 10 Moreover, specific placentitis leads to functional and morphological changes in the placenta with increased risk of stillbirth and neonatal death, 11 predominantly associated with maternal viremia.…”

The sFlt-1/PlGF Ratio in Patients Affected by Gestational Diabetes and SARS-CoV-2 Infection

“…Additionally, it is correlated with maternal comorbidities, with a predominant role being played by obesity and gestational diabetes, which are all proinflammatory conditions [ 9 ]. The link between these comorbidities and the infectivity and virulence of this virus is likely to be caused by glycosylation of the SARS-CoV-2 spike protein; this process may work as a glycan shield, facilitating immune evasion, as well as through spike and Angiotensin-Converting Enzyme 2 (ACE2) interactions [ 10 ]. This association between COVID-19 severity and the serum concentration of the soluble receptor for advanced glycation end-products (sRAGE) was proven in a cohort of 145 adult subjects by Zhao and coworkers [ 11 ].…”