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. 2017 Jul 10;14(1):134.
doi: 10.1186/s12974-017-0907-5.

CXCL11 production in cerebrospinal fluid distinguishes herpes simplex meningitis from herpes simplex encephalitis

Liza Lind  1 , Marie Studahl  2 , Linn Persson Berg  2 , Kristina Eriksson  3
Affiliations

CXCL11 production in cerebrospinal fluid distinguishes herpes simplex meningitis from herpes simplex encephalitis

Liza Lind et al. J Neuroinflammation. .

Abstract

Background: The closely related herpes simplex viruses 1 and 2 can cause inflammations of the central nervous system (CNS), where type 1 most often manifest as encephalitis (HSE), and type 2 as meningitis (HSM). HSE is associated with severe neurological complications, while HSM is benign in adults. We proposed that studying the chemokine and cytokine production in cerebrospinal fluid (CSF) and serum could indicate why two closely related viruses exhibit different severity of their accompanied CNS inflammation.

Methods: Secretion patterns of 30 chemokines and 10 cytokines in CSF of adult patients with acute HSE (n = 14) and HSM (n = 20) in the initial stage of disease were analyzed and compared to control subjects without viral central nervous system infections and to levels in serum.

Results: Most measured chemokines and cytokines increased in CSF of HSE and HSM patients. Overall, the CSF chemokine levels were higher in CSF of HSM patients compared to HSE patients. However, only five chemokines reached levels in the CSF that exceeded those in serum facilitating a positive CSF-serum chemokine gradient. Of these, CXCL8, CXCL9, and CXCL10 were present at high levels both in HSE and HSM whereas CXCL11 and CCL8 were present in HSM alone. Several chemokines were also elevated in serum of HSE patients but only one in HSM patients. No chemokine in- or efflux between CSF and serum was indicated as the levels of chemokines in CSF and serum did not correlate.

Conclusions: We show that HSM is associated with a stronger and more diverse inflammatory response in the CNS compared to HSE in the initial stage of disease. The chemokine patterns were distinguished by the exclusive local CNS production of CXCL11 and CCL8 in HSM. Inflammation in HSM appears to be restricted to the CNS whereas HSE also was associated with systemic inflammation.

Keywords: Chemokine; Cytokine; Encephalitis; Herpes simplex; Meningitis.

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Conflict of interest statement

Ethics approval and consent to participate

The Regional Medical Ethics Committee at Gothenburg University approved the study (No. 552-11) and written informed consent was obtained. The study has been performed in accordance with the ethical standards laid down in Helsinki and its later amendments.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Levels of a CC chemokines, b CXC chemokines, including CX3CL1, and c cytokines in the CSF of healthy control subjects (n = 20–33). Data are presented as individual values with medians indicated by horizontal bars
Fig. 2
Fig. 2
Levels of a CXCL8, b CXCL9, and c CXCL10 in CSF of HSE (n = 14) and HSM (n = 20) patients compared to healthy controls (n = 33) and to serum (n = 8/group; control = 5). Data are presented as individual values with medians indicated by horizontal bars. CSF comparisons were performed using Kruskal-Wallis’ non-parametric test with Dunn’s post-test. White symbols are non-matched CSF or serum samples, which were excluded from analysis of paired CSF and serum (filled symbols), using Wilcoxon matched-pairs signed-rank test. Statistical analysis was performed using GraphPad Prism version 6 (GraphPad Software). Abbreviations: CSF cerebrospinal fluid, HSE herpes simplex encephalitis, HSM herpes simplex meningitis
Fig. 3
Fig. 3
Levels of a CXCL11 and b CCL8 in CSF of HSE (n = 12) and HSM (n = 8) patients compared to healthy controls (n = 20) and to serum (n = 8/group; control = 5). Data are presented as individual values with medians indicated by horizontal bars. CSF comparisons were performed using Kruskal-Wallis’ non-parametric test with Dunn’s post-test. White symbols are non-matched CSF or serum samples, which were excluded from analysis of paired CSF and serum (filled symbols), using Wilcoxon matched-pairs signed rank test. Statistical analysis was performed using GraphPad Prism version 6 (GraphPad Software). Abbreviations: CSF cerebrospinal fluid, HSE herpes simplex encephalitis, HSM herpes simplex meningitis
Fig. 4
Fig. 4
Levels of cytokines in CSF of HSE (n = 12) and HSM (n = 8) patients compared to healthy controls (n = 20–33). a GM-CSF, IFN-γ, IL-1β, IL-2, and IL-4. b IL-10, IL-16, and TNF-α. c IL-6 and MIF. Data are presented as individual values with medians indicated by horizontal bars. CSF comparisons were performed using Kruskal-Wallis’ non-parametric test with Dunn’s post-test in GraphPad Prism version 6 (GraphPad Software). Abbreviations: CSF cerebrospinal fluid, HSE herpes simplex encephalitis, HSM herpes simplex meningitis
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