Targeting the ICAM-1/LFA-1 adhesion axis attenuates lethal Crimean-Congo hemorrhagic fever virus infection

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne bunyavirus. Infection and dysfunction of the vascular endothelium are likely key factors in CCHFV pathogenesis, yet the underlying mechanisms remain poorly understood. Using a mouse model, we demonstrated that CCHFV directly infects vascular endothelium, leading to marked activation and damage, as evidenced by the upregulation of adhesion molecules. To further investigate this phenomenon, we performed a quantitative proteomics study on CCHFV-infected human umbilical vein endothelial cells (HUVECs), confirming a significant upregulation of cell adhesion molecular pathways. Notably, the key adhesion molecule intercellular adhesion molecule 1 (ICAM-1) was prominently induced upon infection, which was transcriptionally dependent on NF-κB. ICAM-1 interacts with its receptor integrin (LFA-1) on leukocytes to mediate firm adhesion and transmigration, thereby driving inflammatory responses. Using an established in vitro adhesion assay, we found that CCHFV infection robustly increased the adhesion of Jurkat T cells to HUVECs. This enhanced adhesion was specifically dependent on ICAM-1, as it was substantially reduced by knockdown of ICAM1 or by competition with its soluble extracellular domain. Moreover, lifitegrast—an approved anti-inflammatory small-molecule antagonist that selectively blocks ICAM-1/LFA-1 interaction, significantly inhibited CCHFV-induced Jurkat T cell adhesion. Importantly, in a lethal murine model of CCHFV infection, the treatment with lifitegrast sodium improved survival rates and concurrently alleviated leukocyte infiltration and tissue damage. These findings delineate an ICAM-1-mediated mechanism of vascular activation and inflammation in CCHFV infection and highlight a promising anti-inflammatory-based strategy for treating CCHF.