The increased concentration of macrophage migration inhibitory factor in serum and cerebrospinal fluid of patients with tick-borne encephalitis

Abstract

Background: Host factors determining the clinical presentation of tick-borne encephalitis (TBE) are not fully elucidated. The peripheral inflammatory response to TBE virus is hypothesized to facilitate its entry into central nervous system by disrupting the blood-brain barrier with the involvement of a signaling route including Toll-like receptor 3 (TLR3) and pro-inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNFα), and interleukin-1 beta (IL-1β). Methods: Concentrations of MIF, TNFα, and IL-1β were measured with commercial ELISA in serum and cerebrospinal fluid (CSF) from 36 hospitalized TBE patients, 7 patients with non-TBE meningitis, and 6 controls. The CSF albumin quotient (AQ) was used as a marker of blood-brain barrier permeability. Single nucleotide polymorphisms rs3775291, rs5743305 (associated with TLR3 expression), and rs755622 (associated with MIF expression) were assessed in blood samples from 108 TBE patients and 72 non-TBE controls. The data were analyzed with non-parametric tests, and p < 0.05 was considered significant. Results: The median serum and CSF concentrations of MIF and IL-1β were significantly increased in TBE group compared to controls. MIF concentration in serum tended to correlate with AQ in TBE, but not in non-TBE meningitis. The serum concentration of TNFα was increased in TBE patients bearing a high-expression TLR3 rs5743305 TT genotype, which also associated with the increased risk of TBE. The low-expression rs3775291 TLR3 genotype TT associated with a prolonged increase of CSF protein concentration. The high-expression MIF rs755622 genotype CC tended to correlate with an increased risk of TBE, and within TBE group, it was associated with a mild presentation. Conclusions:The results point to the signaling route involving TLR3, MIF, and TNFα being active in TBE virus infection and contributing to the risk of an overt neuroinvasive disease. The same factors may play a protective role intrathecally contributing to the milder course of neuroinfection. This suggests that the individual variability of the risk and clinical presentation of TBE might be traced to the variable peripheral and intrathecal expression of the mediators of the inflammatory response, which in turn associates with the host genetic background.

The intrathecal expression and pathogenetic role of Th17 cytokines and CXCR2-binding chemokines in tick-borne encephalitis

“…This forms a likely route of the initial CNS entry during the peripheral phase, but additional migration mechanisms that could increase CNS viral load are possible and supported by mouse WNV encephalitis models [ 7 – 9 ]. Previously, we have studied the postulated mode of CNS entry following BBB disruption by a systemic inflammatory response mediated by macrophage migration inflammatory factor (MIF) and tumor necrosis factor alpha (TNFα)––a mechanism that seems feasible but remains unproven and does not exclude the existence of other pathogenically and clinically relevant routes of infection [ 61 ]. The current results are consistent with the alternative possibility of the migration of the infected neutrophils dependent on intrathecal IL-22 and CXCL1 as a clinically important route of TBEV entry into CNS.…”

Tick-Borne Flaviviruses and the Type I Interferon Response

“…What we are aware of; no animal experiments have shown any significance of the TLR3-TRIF pathway in tick-borne flavivirus infection. However, several studies have looked at the prevalence of polymorphisms in the TLR3 gene in TBE patients [ 133 , 134 , 135 , 136 ]. In particular, one polymorphism has been investigated the T allele in rs3775291.…”

“…This polymorphism has been shown to reduce TLR3 signaling by about 30% [ 137 ]. Although the data regarding TLR3 is somewhat conflicting, Grygorczuk et al hypothesized that a functional TLR3 facilitates the onset of neurological disease [ 135 ] by supporting the penetration through the blood brain barrier, but has a protective effect during the established CNS infection [ 134 ]. The differences between studies might also be connected to the different subtypes of the TBEV strain and the genetic background of the studied populations [ 134 ].…”

Macrophage Migration Inhibitory Factor Alters Functional Properties of CA1 Hippocampal Neurons in Mouse Brain Slices

“…Following CNS insults such as stroke, spinal cord injury and TBI, MIF concentration is elevated within cells, CSF and serum. MIF is also found to be elevated in numerous neuroinflammatory and neurodegenerative diseases, including: Multiple sclerosis, meningitis, encephalitis tick-borne borreliosis, subarachnoid hemorrhage, and Alzheimer's disease [15][16][17][18][19][20][21][22][23][24][25][26][27]. Thus, MIF may be an important protein to examine as both a prognostic indicator of, and possible therapeutic target for TBI, numerous neuroinflammatory conditions, and Alzheimer's disease.…”