Extracellular vesicle proteomics and phosphoproteomics identify pathways for increased risk in patients hospitalized with COVID-19 and type 2 diabetes mellitus

Highlights

• Plasma EV cargo reflects the pathological condition in patients with COVID-19 and T2D.

• Activation of PKC, AMPK, MAPK, and SYK kinases contribute to the COVID-19 by T2D interaction.

• Circulating C1Q + EVs may spread immuno-modulatory and prothrombotic cargo.

• EV-shuttled CASP3 and ROCK1 may contribute to overactivation of macrophages and inflammation.

• Inhibitors of PKCβ, ROCK1, and SYK kinases may be promising therapeutic options against COVID-19.

Abstract

Recent studies suggest that extracellular vesicles (EVs) play a role in the pathogenesis of SARS-CoV-2 infection and the severity of COVID-19. However, their role in the interaction between COVID-19 and type 2 diabetes (T2D) has not been addressed. Here, we characterized the circulating EV proteomic and phosphoproteomic landscape in patients with and without T2D hospitalized with COVID-19 or non-COVID-19 acute respiratory illness (RSP). We detected differentially expressed protein and phosphoprotein signatures that effectively characterized the study groups. The trio of immunomodulatory and coagulation proteins C1QA, C1QB, and C1QC appeared to be a central cluster in both the COVID-19 and T2D functional networks. PKCβ appeared to be retained in cells by being diverted from EV pathways and contribute to the COVID-19 and T2D interaction via a PKC/BTK/TEC axis. EV-shuttled CASP3 and ROCK1 appeared to be coregulated and likely contribute to disease interactions in patients with COVID-19 and T2D. Predicted activation of AMPK, MAPK, and SYK appeared to also play important roles driving disease interaction. These results suggest that activated cellular kinases (i.e., PKC, AMPK, MAPK, and SYK) and multiple EV-shuttled kinases (i.e., PKCβ, BTK, TEC, MAP2K2, and ROCK1) may play key roles in severe COVID-19, particularly in patients with comorbid diabetes.