Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection

Abstract

BackgroundTick-borne encephalitis (TBE) is a severe neuropathological disorder caused by tick-borne encephalitis virus (TBEV). Brain TBEV infection is characterized by extensive pathological neuroinflammation. The mechanism by which TBEV causes CNS destruction remains unclear, but growing evidence suggests that it involves both direct neuronal damage by the virus infection and indirect damage caused by the immune response. Here, we aimed to examine the TBEV-infection-induced innate immune response in mice and in human neural cells. We also compared cytokine/chemokine communication between naïve and infected neuronal cells and astrocytes.MethodsWe used a multiplexed Luminex system to measure multiple cytokines/chemokines and growth factors in mouse serum samples and brain tissue, and in human neuroblastoma cells (SK-N-SH) and primary cortical astrocytes (HBCA), which were infected with the highly pathogenic TBEV strain Hypr. We also investigated changes in cytokine/chemokine production in naïve HBCA cells treated with virus-free supernatants from TBEV-infected SK-N-SH cells and in naïve SK-N-SH cells treated with virus-free supernatants from TBEV-infected HBCA cells. Additionally, a plaque assay was performed to assess how cytokine/chemokine treatment influenced viral growth following TBEV infection.ResultsTBEV-infected mice exhibited time-dependent increases in serum and brain tissue concentrations of multiple cytokines/chemokines (mainly CXCL10/IP-10, and also CXCL1, G-CSF, IL-6, and others). TBEV-infected SK-N-SH cells exhibited increased production of IL-8 and RANTES and downregulated MCP-1 and HGF. TBEV infection of HBCA cells activated production of a broad spectrum of pro-inflammatory cytokines, chemokines, and growth factors (mainly IL-6, IL-8, CXCL10, RANTES, and G-CSF) and downregulated the expression of VEGF. Treatment of SK-N-SH with supernatants from infected HBCA induced expression of a variety of chemokines and pro-inflammatory cytokines, reduced SK-N-SH mortality after TBEV infection, and decreased virus growth in these cells. Treatment of HBCA with supernatants from infected SK-N-SH had little effect on cytokine/chemokine/growth factor expression but reduced TBEV growth in these cells after infection.ConclusionsOur results indicated that both neurons and astrocytes are potential sources of pro-inflammatory cytokines in TBEV-infected brain tissue. Infected/activated astrocytes produce cytokines/chemokines that stimulate the innate neuronal immune response, limiting virus replication, and increasing survival of infected neurons.

Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein‐positive cells and microglia in male mice

“…Interaction and treatment effects with multiple comparisons were carried out using two-way analysis of variance ( the identity of cells hosting these regulations. In the literature, the source of production of these molecules is still debated because of the involvement of several cell types including microglia, astrocytes, oligodendroglia, neurons, cerebrovascular cells, and circulating immune cells (Pokorna Formanova et al, 2019;Ramesh, MacLean, & Philipp, 2013).…”

“…This result leads us to question the identity of cells hosting these regulations. In the literature, the source of production of these molecules is still debated because of the involvement of several cell types including microglia, astrocytes, oligodendroglia, neurons, cerebrovascular cells, and circulating immune cells(Pokorna Formanova et al, 2019;Ramesh, MacLean, & Philipp, 2013).The decrease of cytokine gene expression after targeted pharmacogenetic manipulation of GFAP-positive cells makes us assume that astrocytes play an important role in the postprandial upregulation of cytokines expression in the HT. However, due to complex cell interactions in the brain, it is possible that astrocytes are not directly the source of these cytokines.…”

CD8+ T cells in the central nervous system of mice with herpes simplex infection are highly activated and express high levels of CCR5 and CXCR3

“…IFN-gamma, which we could show is expressed in the infected spinal cord, induces the expression of CXCL10. CXCL10 is also upregulated in other neuroinflammatory infections like Theiler’s murine encephalomyelitis virus, lymphocytic choriomeningitis virus, and tick-borne encephalitis (Hoffman et al 1999 ; Nansen et al 2000 ; Pokorna Formanova et al 2019 ). Most importantly, the enhanced levels of CXCL10 correlate with data from cerebrospinal fluid from humans with HSV-2 meningitis (Lind, Studahl et al 2017 ).…”

Low-pathogenic virus induced immunity against TBEV protects mice from disease but not from virus entry into the CNS

“…Therefore, it remains unclear whether detected signal resulted from infection of Iba1-positive cells or from phagocytosis. There is evidence that neurotropic flaviviruses can influence the behavior of microglia and astrocytes and either assist in viral clearance or augment neuropathogenesis by producing toxic neuroinflammatory mediators (17,20,28–30). To avoid any permanent damage, inflammation within the CNS is highly regulated and is primarily mediated by microglia and astrocytes.…”