engleski

Immunological markers in neuroinvasive arboviral infections

Objectives: Literature data on the immunopathogenesis of neuroinvasive arboviral infections, particularly in the context of complex cytokine immune responses, are limited. The aim of this study was to compare cytokine expression patterns in the cerebrospinal fluid (CSF) and serum in human neuroinvasive arboviral infections caused by tick-borne encephalitis virus (TBEV), West Nile virus (WNV) and Toscana virus (TOSV). Methods: Antiviral cytokine response in the serum and CSF was analysed by using a multiplex bead- based assay for simultaneous quantification of 13 human cytokines (LEGENDplex Human Th cytokine panel, BioLegend, USA) on FACS Canto II flow cytometer (Beckton Dickinson, USA). The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α, IL-6), Th1 type immune response (IL-2, IFN-γ), Th2 immune response (IL-4, IL-5, IL-9 and IL-13), Th17 immune response (IL-17A, IL-17F, IL-21 and IL-22) and the key anti-inflammatory cytokine IL-10. Results: Analysis of cytokine expression pattern in the CSF and serum of patients with neuroinvasive infection with TBEV (32 patients), WNV (68 patients) and TOSV (3 patients) revealed partially similar patterns. Significantly higher concentrations of IL-6 in the CSF vs. serum were found in both TBEV (median 780.88 pg/mL, IQR 130.81-3, 077.66 vs. median 23.25 pg/mL, IQR 7.79- 27.09, respectively ; p<0.001) and WNV (median 2, 036.71 pg/mL, IQR 213.82-6, 190.5 vs. median 24.48 pg/mL, IQR 11.93-49.81, respectively ; p<0.001) patient groups. Similarly, higher concentrations of IFN-γ in the CSF compared with serum have been shown in both TBEV (median 122.7 pg/mL, IQR 98.09- 246.04 vs. 27.28 pg/mL, IQR 14.81-37.75 ; p<0.001) and WNV patient groups (median 49.59 pg/mL, IQR 23.07-127.37 vs. 27.22 pg/mL, IQR 20.95-41.82 ; p=0.07). Expression of IL-2, IL-4, TNF-α and Th1 17 cytokines (IL-17A, IL-17F, IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F and IL-4). Th1 cytokine IL-13 was detectable in both serum and CSF of WNV patients but only in the serum of TBEV patients. In contrast, IL-22 and IL-5 were detectable in both serum and CSF of TBEV patients but only in the serum of WNV patients (except one positive CSF sample for IL-5). CSF samples of patients with Toscana neuroinvasive disease showed higher concentrations of IL-6, IFN-γ and IL-10 compared with corresponding serum samples. Conclusions: The results of this study show increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) in the CNS of patients with neuroinvasive arbovirus infections. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery. These findings suggest a well- defined pattern of cytokine biology in neuroinvasive arboviral infections. Further studies on the possible association between cytokine expression patterns and clinical severity of WNV, TBEV and TOSV neuroinvasive infections as well as on the underlying mechanisms of cellular immunity warrant further investigations.

immunological markers ; tick-borne encephalitis virus ; West Nile virus ; Toscana virus

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