BACKGROUND: Tick-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. METHODS: We 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. RESULTS: TBEV-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. CONCLUSIONS: Our 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.

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 61300 Brno Czech Republic

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branisovska 31 CZ 37005 Ceske Budejovice Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc20023497

003      

CZ-PrNML

005      

20230815111905.0

007      

ta

008      

201125s2019 xxk f 000 0|eng||

009      

AR

024    7_

$a 10.1186/s12974-019-1596-z $2 doi

035    __

$a (PubMed)31699097

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxk

100    1_

$a Pokorna Formanova, Petra $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.

245    10

$a Changes in cytokine and chemokine profiles in mouse serum and brain, and in human neural cells, upon tick-borne encephalitis virus infection / $c P. Pokorna Formanova, M. Palus, J. Salat, V. Hönig, M. Stefanik, P. Svoboda, D. Ruzek,

520    9_

$a BACKGROUND: Tick-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. METHODS: We 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. RESULTS: TBEV-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. CONCLUSIONS: Our 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.

650    _2

$a zvířata $7 D000818

650    _2

$a mozek $x imunologie $x metabolismus $x patologie $7 D001921

650    _2

$a cytokiny $x imunologie $x metabolismus $7 D016207

650    _2

$a klíšťová encefalitida $x imunologie $x metabolismus $7 D004675

650    _2

$a lidé $7 D006801

650    _2

$a myši $7 D051379

650    _2

$a neurony $x imunologie $x metabolismus $x virologie $7 D009474

655    _2

$a časopisecké články $7 D016428

700    1_

$a Palus, Martin $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic. Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005, Ceske Budejovice, Czech Republic.

700    1_

$a Salat, Jiri $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.

700    1_

$a Hönig, Václav, $d 1982- $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic. Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005, Ceske Budejovice, Czech Republic. $7 jcu2012681186

700    1_

$a Stefanik, Michal $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic. Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-61300, Brno, Czech Republic.

700    1_

$a Svoboda, Pavel $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.

700    1_

$a Růžek, Daniel, $d 1981- $u Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic. ruzekd@paru.cas.cz. Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005, Ceske Budejovice, Czech Republic. ruzekd@paru.cas.cz. $7 stk2008441707

773    0_

$w MED00163330 $t Journal of neuroinflammation $x 1742-2094 $g Roč. 16, č. 1 (2019), s. 205

856    41

$u https://pubmed.ncbi.nlm.nih.gov/31699097 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20201125 $b ABA008

991    __

$a 20230815111902 $b ABA008

999    __

$a ok $b bmc $g 1595816 $s 1114173

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2019 $b 16 $c 1 $d 205 $e 20191107 $i 1742-2094 $m Journal of neuroinflammation $n J Neuroinflammation $x MED00163330

GRA    __

$a 16-34238A $p Ministry of Health of the Czech Republic

GRA    __

$a NV19-05-00457 $p Ministerstvo Zdravotnictví Ceské Republiky

GRA    __

$a NV16-34238A $p MZ0

LZP    __

$a Pubmed-20201125