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

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. PKC beta 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 SYF appeared to also play important roles driving disease interaction. These results suggest that activated cellular kinases (i.e., PKC, AMPK, MAPK, and SYF) and multiple EV-shuttled kinases (i.e., PKC beta, BTK, TEC, MAP2K2, and ROCK1) may play key roles in severe COVID-19, particularly in patients with comorbid diabetes.

Automated summary

Recent studies indicate that extracellular vesicles (EVs) are involved in the development of SARS-CoV-2 infection and the severity of COVID-19. However, the connection between COVID-19 and type 2 diabetes (T2D) in relation to EVs has not been explored. This study examined the proteomic and phosphoproteomic profiles of circulating EVs in hospitalized patients with and without T2D, who had either COVID-19 or non-COVID-19 acute respiratory illness (RSP). Differential expression of certain proteins and phosphoproteins was observed, with a central cluster of immunomodulatory and coagulation proteins (C1QA, C1QB, and C1QC) identified in both COVID-19 and T2D networks. The study also revealed the involvement of cellular kinases and EV-shuttled kinases in severe COVID-19, particularly in patients with comorbid diabetes.