Increased levels of soluble forms of E-selectin and ICAM-1 adhesion molecules during human leptospirosis

Abstract

Leptospirosis is a multisystemic zoonotic disease with infiltration of visceral organs by Leptospira. The capacity of the vascular endothelium to grant immune cell recruitment and activation in target organs during the disease course remains poorly characterized. We ascertained the levels of expression of several soluble cell adhesion molecules (CAM) notably expressed by endothelial cells in human leptospirosis. We prospectively enrolled 20 hospitalized patients and compared them to 10 healthy controls. Disease severity was defined by one or more organ failures, or death. Plasmatic concentrations of soluble CAM were assessed by multiplex bead assay at the time of patient presentation (M0) and 1 month after hospital discharge. The levels of soluble E-selectin (sCD62E) and soluble intercellular adhesion molecule 1 (sICAM-1, sCD53) were significantly increased in patients compared to controls (p<0.0001) and at 1 month (p<0.0001) with median values at 978 ng/ml (interquartile ranges 787-1164; sCD62E) and 1021 ng/ml (690-1428; sCD53). At M0, Soluble P-selectin level (sCD62P) was found to be decreased with levels at 60 ng/ml (0-631) versus 711 ng/ml (343-1113) for healthy controls (p<0.05). Levels of sICAM-3 (sCD50), sVCAM-1 (vascular cell adhesion molecule, sCD106) and sPECAM-1 (platelet endothelial cell adhesion molecule, sCD31) were not different from healthy subjects at M0. This study shows that two adhesion molecules, shed as soluble forms, are elevated during the acute phase of leptospirosis: E-selectin and s-ICAM1. These molecules may interfere with the process of immune cell recruitment to clear Leptospira at tissue levels.

Fig 1. Correction of blood cell counts and tissue-injury biomarkers at 1 month post-leptospirosis.

Evolution of blood cell counts and surrogate biomarkers of tissue injury between acute (M0, empty circles) and convalescent phase, 1 month later (M1, black circles) for 10 patients. Gray areas indicate normal values ranges. Two values for M1 patient CPK (creatine phosphokinase) measurement could not be included. Comparisons with non-parametric Wilcoxon paired test. * and ** indicate P-value inferior to 0.05 and 0.01 respectively.

Fig 2. Levels of soluble E-selectin and soluble ICAM-1 are increased during the acute phase of human leptospirosis.

Levels of soluble (shed) adhesion molecules are determined in patients and controls using multiplex microbeads array. Circles represent controls (n = 10), empty triangles: patients during acute phase (n = 20) and black triangles: patients at M1 convalescent phase (n = 10). The largest horizontal bars indicate the median value, upper and lower bars the interquartile ranges. Comparisons with non-parametric Mann-Whitney test. *, **, **** indicate P-value inferior to 0.05, 0.01 and 0.0001 respectively.

Fig 3. Distinct associations between shed adhesion molecules and organ injuries in 20 leptospirosis patients.

Levels of soluble (shed) adhesion molecules are determined among leptospirosis M0 group (n = 20) using multiplex microbeads array. The largest horizontal bars indicate the median value, upper and lower bars the interquartile ranges. Comparisons with non-parametric Mann-Whitney test. * and ** indicate P-value inferior to 0.05 and 0.01 respectively. CPK = creatine phosphokinase; ULR = upper limit range.