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. 2021 Jul 1:11:696337.
doi: 10.3389/fcimb.2021.696337. eCollection 2021.

Upregulated Intrathecal Expression of VEGF-A and Long Lasting Global Upregulation of Proinflammatory Immune Mediators in Vaccine Breakthrough Tick-Borne Encephalitis

Miša Pavletič  1 , Misa Korva  1 , Nataša Knap  1 , Petra Bogovič  2 , Lara Lusa  3   4 , Klemen Strle  5 , Mirijam Nahtigal Klevišar  2 , Tomaž Vovko  2 , Janez Tomažič  2 , Stanka Lotrič-Furlan  2 , Franc Strle  2 , Tatjana Avšič-Županc  1
Affiliations

Upregulated Intrathecal Expression of VEGF-A and Long Lasting Global Upregulation of Proinflammatory Immune Mediators in Vaccine Breakthrough Tick-Borne Encephalitis

Miša Pavletič et al. Front Cell Infect Microbiol. .

Abstract

Although anti-TBE vaccines are highly effective, vaccine breakthrough (VBT) cases have been reported. With increasing evidence for immune system involvement in TBE pathogenesis, we characterized the immune mediators reflecting innate and adaptive T and B cell responses in neurological and convalescent phase in VBT TBE patients. At the beginning of the neurological phase, VBT patients have significantly higher serum levels of several innate and adaptive inflammatory cytokines compared to healthy donors, reflecting a global inflammatory state. The majority of cytokines, particularly those associated with innate and Th1 responses, are highly concentrated in CSF and positively correlate with intrathecal immune cell counts, demonstrating the localization of Th1 and proinflammatory responses in CNS, the site of disease in TBE. Interestingly, compared to unvaccinated TBE patients, VBT TBE patients have significantly higher CSF levels of VEGF-A and IFN-β and higher systemic levels of neutrophil chemoattractants IL-8/CXCL8 and GROα/CXCL1 on admission. Moreover, serum levels of IL-8/CXCL8 and GROα/CXCL1 remain elevated for two months after the onset of neurological symptoms, indicating a prolonged systemic immune activation in VBT patients. These findings provide the first insights into the type of immune responses and their dynamics during TBE in VBT patients. An observed systemic upregulation of neutrophil derived inflammation in acute and convalescent phase of TBE together with highly expressed VEGF-A could contribute to BBB disruption that facilitates the entry of immune cells and supports the intrathecal localization of Th1 responses observed in VBT patients.

Keywords: VEGF; chemokines; cytokines; proinflammatory response; tick-borne encephalitis; vaccine breakthrough.

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Conflict of interest statement

PB served on the scientific advisory board for Pfizer on TBE CEE expert meeting 2020. KS served on the scientific advisory board for Roche for development of Lyme disease serological diagnostics received support by grant from MGH-ECOR. FS served on the scientific advisory board for Roche on Lyme disease serological diagnostics and the scientific advisory board for Pfizer on TBE CEE expert meeting 2020, has been a member of Pfizer Lyme Vaccine Licensure Advisory Board, received research support from the Slovenian Research Agency [grant number P3-0296], and is an unpaid member of the steering committee of the ESCMID Study Group on Lyme Borreliosis/ESGBOR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Serum concentrations of 35 immune mediators in VBT patients (VBT; n = 41) and age and gender matched healthy individuals (Healthy; n = 42). For VBT patients, cytokine and chemokine concentrations measured in serum samples obtained at the onset of neurological symptoms are presented. Concentrations of immune mediators are in pg/ml, except those, marked with an asterisk are in ng/ml. The box and whisker plots show the median (vertical line), quartiles (box) and the whiskers, which extend to the most extreme data point which is no more than 1.5 times the interquartile range from the box; the data points outside of this range are plotted individually. Innate immune mediators: GM-CSF, IFN-α2, GROα/CXCL1, IL-10, IL-15, IL-1RA, IL-1β, IL-6, IL-8, MCP-1/CCL2, MIP-1α/CCL3, TNF-α, VEGF-A, MIP-3β/CCL19, IFN-β; Th1 immune mediators: IFN-γ, IL-12 (p40), IL-2, MIG/CXCL9, IFN-λ3/IL-28B, IP-10/CXCL10, I-TAC/CXCL11; Th2 immune mediators: IL-4, IL-5; Th17 immune mediators: IL-17A, IL-17F, IL-22, IL-21, IL-23, IL-17E, IL-27; B cell immune mediators: BCA-1/CXCL13, SDF-1α+β/CXCL12, BAFF, APRIL.
Figure 2
Figure 2
A heatmap illustrating concentrations of 35 cytokines and chemokines measured in serum and CSF of 41 VBT patients. Cytokine concentrations are visually presented on a log10 scale with red and green indicating high and low expression, respectively (refer to color bar).
Figure 3
Figure 3
The concentrations of immune mediators that significantly differed in (A) CSF or (B) serum samples between VBT TBE patients (VBT TBE; n=41) and in age and gender matched unvaccinated TBE patients (Unvaccinated TBE; n=81) obtained at the onset of neurological symptoms.
Figure 4
Figure 4
The concentrations of 35 immune mediators in serum samples of healthy individuals (H) and VBT TBE patients obtained on admission to the hospital (S1; n = 41), two to three weeks later (S2; n = 18) and one to two months (S3; n = 24) after the onset of neurological symptoms. Concentrations of immune mediators are in pg/ml, except those, marked with an asterisk are in ng/ml. Innate immune mediators: GM-CSF, IFN-α2, GROα/CXCL1, IL-10, IL-15, IL-1RA, IL-1β, IL-6, IL-8, MCP-1/CCL2, MIP-1α/CCL3, TNF-α, VEGF-A, MIP-3β/CCL19, IFN-β; Th1 immune mediators: IFN-γ, IL-12 (p40), IL-2, MIG/CXCL9, IFN-λ3/IL-28B, IP-10/CXCL10, I-TAC/CXCL11; Th2 immune mediators: IL-4, IL-5; Th17 immune mediators: IL-17A, IL-17F, IL-22, IL-21, IL-23, IL-17E, IL-27; B cell immune mediators: BCA-1/CXCL13, SDF-1α+β/CXCL12, BAFF, APRIL.
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