Antimicrobial Peptide LL‑37 Contributes to Thrombotic Complications in Patients With COVID‑19

According to research published in Cellular and Molecular Life Sciences, a cathelicidin antimicrobial peptide, LL-37, appears to be elevated during SARS-CoV-2 infection and may contribute to hypercoagulation in patients with COVID-19.

Researchers evaluated the role of LL-37 in patients with confirmed COVID-19 at the Chongqing Public Health Medical Center and Department of Infectious Diseases, Southwest Hospital, Third Military Medical University in China.

They analyzed coagulation function, including prothrombin and thrombin time (PT and TT), activated partial thromboplastin time (APTT), and fibrinogen level as well as levels of LL-37 in the plasma of patients with COVID-19 and control participants without COVID-19 (HC). The team also evaluated the mechanism of action of LL-37 in human alveolar basal epithelial cells and a murine model.

A total of 62 patients with COVID-19 and 21 age- and sex-matched controls without COVID-19 were included in the study. Patients with COVID-19 were divided into mild or moderate (MM; n=40) and severe/critical (SC; n=22) groups.

Compared with HCs, patients with COVID-19 showed shortened TT (HC, 17.96±0.98 s; MM, 14.60±0.79 s; SC, 15.43±1.37 s; P <.001 for HC vs MM and HC vs SC) and increased fibrinogen levels (HC, 2.81±0.48 g/L; MM, 4.21±0.83 g/L; SC, 4.81±0.98 g/L; P <.001 for HC vs MM and HC vs SC). PT was not significantly different between the groups (HC, 11.53±0.52 s; MM, 12.00±0.80 s; SC, 12.06±1.29 s), but APTT was significantly longer in the patients with COVID-19 compared with HCs (HC, 29.44±3.52 s; MM, 41.35±4.48 s; SC, 38.70±9.63 s; P <.001 for HC vs MM and HC vs SC).

Patients with COVID-19 had elevated plasma levels of LL-37 compared with HCs (MM, 140±46.47 ng/ml; SC, 147.6±64.24 ng/ml; HC, 93.62±48.14 ng/ml; P<.01 for HC vs MM and HC vs SC).

The researchers demonstrated that incubation of the SARS-CoV-2 spike protein at different concentrations (0.4, 2, and 10 μg/ml) with human alveolar basal epithelial cells significantly increased their hCAP18 (the precursor of LL-37) expression (control vs 2 μg/ml; P <.05 and control vs 10 μg/ml; P <.01).

They also showed that incubation of SARS-CoV-2 at different multiplicity of infection ratios (0.01, 0.05, and 0.25) with human alveolar basal epithelial cells significantly increased their LL-37 levels (control vs 0.05 and control vs 0.25; P <.001 for both).

In an FeCl3-induced carotid artery thrombosis mouse model, the team demonstrated that injection of LL-37 promoted thrombosis formation and shortened the time of arterial occlusion. They also found that LL-37 administration directly induced lung thrombosis, while deleting the mouse LL-37 gene inhibited thrombosis in the mouse model.

“These results suggest that cathelicidin antimicrobial peptide LL-37 is elevated during SARS-CoV-2 infection, which may induce hypercoagulation in COVID-19 patients by activating coagulation factors,” concluded the authors.

Reference

Duan Z, Zhang J, Chen X, et al. Role of LL-37 in thrombotic complications in patients with COVID-19. Cell Mol Life Sci. Published online May 21, 2022. doi:10.1007/s00018-022-04309-y

This article originally appeared on Hematology Advisor